Clin Pharmacokinet DOI 10.1007/s40262-015-0259-1
LEADING ARTICLE
Altered Drug Disposition Following Bariatric Surgery: A Research Challenge H. Karl Greenblatt1 • David J. Greenblatt1
Ó Springer International Publishing Switzerland 2015
Abstract Bariatric surgery constitutes an approach to the management of obesity in which the anatomy of the gastrointestinal tract is altered to reduce access of nutrients to absorptive surfaces, to restrict the absolute volume of material that can be ingested at once, or a combination of the two. Roux-en-Y gastric bypass (RYGB), currently the most common bariatric surgical procedure worldwide, has both malabsorptive and restrictive features. RYGB can be associated with alterations in absorption and disposition of medications. However documenting and predicting the specific pharmacokinetic changes associated with RYGB is a difficult research challenge. Because obesity and weight loss themselves can alter drug disposition, it may be difficult or impossible to resolve whether pharmacokinetic alterations in post-RYGB patients are due to the surgery itself as opposed to the subsequent weight loss. Changes in disposition of medications may be drug-specific as opposed to generalized. Further, statistically significant modifications in drug disposition are not necessarily of clinical importance. Clinical decisions on medication use in postbariatric surgical patients should be based on a review of the original literature dealing with the particular drug in question.
& David J. Greenblatt [email protected] 1
Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
Key Points Alterations in drug disposition in post-bariatric surgical patients can be due to a combination of altered gastrointestinal tract anatomy and physiology, together with the effects of subsequent weight loss. No valid paradigm is available to predict the specific changes in drug absorption and clearance associated with bariatric surgery, the magnitude of the changes, and whether they are clinically important. Clinical decisions on medication use in these patients should be based on a review of the original literature dealing with the particular drug in question.
1 Introduction Obesity is a significant worldwide public health concern [1]. As of 2008, approximately one-third of the US population was considered obese, with a body mass index (BMI) of 30 kg/m2 or higher [2, 3]. In obese patients, the most common comorbid conditions include glucose intolerance and type 2 diabetes, hypertension, lipid disorders, coronary artery disease, and joint damage. The most recent US data from the National Health and Nutrition Examination Survey indicate that the prevalence of obesity has stabilized over the last 10 years [3]. This is an encouraging trend, but obesity nonetheless continues to be a public health problem of high prevalence (Fig. 1).
H. K. Greenblatt, D. J. Greenblatt
Fig. 1 Fraction of the adult American population with body mass index (BMI) values exceeding 30, 35 and 40 kg/m2. The data are from the 2011–2012 National Health and Nutrition Examination Survey [3]
Bariatric surgery is an available option for obese individuals to achieve and sustain weight loss [4–6]. The estimated number of bariatric procedures performed worldwide increased from 146,000 in 2003 to about 344,000 in 2008 [4, 7, 8]. The numbers were nearly identical in 2011. A similar trend was seen in North America between 2003 and 2008 (from 103,000 up to 220,000). However, by 2011, the number had decreased dramatically to 102,000. Also evident are changes over time in the types of procedure performed [4, 7, 8]. The Roux-en-Y gastric bypass (RYGB) remains the most common procedure worldwide, though its use in the USA has declined considerably since 2008. Adjustable gastric banding (AGB) is also diminishing in popularity, and procedures such as biliopancreatic diversion/duodenal switch, mini gastric bypass, and vertical banded gastroplasty are done uncommonly. Sleeve gastrectomy (SG) has rapidly increased in popularity, going from 18,000 procedures worldwide in 2008 to 95,000 in 2011. A general trend to laparoscopic approaches is observed overall, probably because of the lower level of invasiveness, accelerated recovery, reduction in complications, and reduced postoperative pain. Bariatric surgical procedures are generally classified as either restrictive or malabsorptive [4–6]. Restrictive procedures reduce the volume of the stomach, thereby limiting the net volume that an individual can ingest at one time. Malabsorptive procedures reduce the available intestinal surface area, thereby reducing the net area available for drug and nutrient absorption. RYGB—still the most common of the bariatric procedures—is both restrictive and malabsorptive; the small intestine is reconnected to a 30–60 mL gastric pouch, bypassing the duodenum, jejunum, and most
of the ileum. RYGB leaves the patient with a substantially reduced absorptive surface area. The effectiveness of RYGB in producing weight loss has been demonstrated repeatedly [9, 10]. In a review of available clinical trials, Chang et al. [10] reported a mean loss of 41–62 % of excess weight at 5 years after surgery. It is not surprising that an anticipated complication of RYGB is malabsorption of nutrients and vitamins. A parallel concern is the possibility that RYGB, independently of whether weight loss occurs, alters the absorption, distribution, and clearance of drugs. Obesity and surgery both predispose individuals to comorbidities that require pharmacological management, so any changes in drug metabolism and disposition might disproportionately affect outcomes in RYGB patients. The purpose of this article is to examine the evidence for pharmacokinetic alterations associated with bariatric surgery, and whether such changes, if they occur, are of clinical or therapeutic importance. Most of the available research data relates to RYGB and other predominantly malabsorptive procedures. Given the emergent popularity of predominantly restrictive procedures such as laparoscopic SG, there is a need for data on drug disposition changes associated with this category of bariatric surgery.
2 Drug Disposition Following Bariatric Surgery: Framing the Research Questions The physiological bases for post-RYGB changes in the pharmacokinetic behaviour of drugs can be categorized as those resulting from the procedure itself, and those that stem from subsequent weight loss. In principle, these are distinct and independent, though they generally co-exist in bariatric surgery patients. Resolution of the separate underlying mechanism for pharmacokinetic changes, and ultimately understanding the net clinical and therapeutic implications, requires close attention to the research questions and to the construction of research designs. There is extensive research data available on the effects of obesity on drug distribution and clearance [11–17]. Nearly all of this work is based on comparisons of cohorts of obese individuals with parallel cohorts of ‘normalweight’ controls, often matched according to age and gender. Generally the control population in cohort studies of this type has never been significantly obese, and has not experienced extensive weight loss. These cohort comparisons do not constitute studies of weight loss, in which drug disposition is evaluated in the same individual first during obesity, and again after weight loss. It cannot be assumed that features of body composition and drug disposition are identical between individuals who were formerly obese before becoming ‘normal’ in body weight, as opposed to
Drug Disposition and Bariatric Surgery
subjects who were never obese. Ironically, nearly all studies of drug disposition following weight loss involve individuals who have had bariatric surgery, thereby thwarting the objective of resolving the effects of surgery from those of weight loss. Similar methodological problems complicate study of the pharmacokinetic consequences of the surgical procedure itself, independent of weight loss. RYGB creates a small gastric pouch (reduction in stomach volume), and loss of functional intestinal surface area—changes likely to be permanent. In principle, these anatomical changes could affect the rate and extent of drug absorption, enteric metabolism, enteric efflux transport, hepatic presystemic extraction, and net hepatic clearance. Oral and/or parenteral drug disposition could be studied in the same individuals before and shortly after bariatric surgery, but this is a study of surgical effects in patients who are still obese. If enough time passes to allow significant weight loss, the study becomes an evaluation of surgery plus weight loss. A cohort study of post-surgical patients who have attained normal weight compared to never-obese non-surgical controls still has the potential confounding problem described above. RYGB surgery for indications other than obesity is likely to be rare, so there is a low probability of encountering post-RYGB patients who have not undergone weight loss. In the context of bariatric surgery, the physiological and pharmacokinetic consequences of the surgical procedure itself are necessarily mingled with the consequences of obesity and of weight loss. A combination of longitudinal and cohort designs probably constitutes the most reasonable overall research strategy. For the longitudinal component, the kinetics of the target drug are determined in the same individual first prior to surgery, again in the proximal postoperative period before significant weight loss has occurred, and finally after time has elapsed and body weight has been reduced. The cohort component would involve study of post-surgical patients who have attained ‘normal’ weight compared to individuals of comparable body weight and habitus who have not had surgery, have never been obese, and have not lost weight.
3 Enteric Anatomy and Physiology Following Roux-en-Y Gastric Bypass Surgery It could be speculated that RYGB would decrease the absorption of all drugs simply through loss of surface area. However the determinants of drug absorption are complex, and the straightforward assumption is not generally valid. The rate and extent of drug absorption are independent and not necessarily related [18]. Absorption rate relates to how fast a drug reaches the systemic circulation after oral
administration, regardless of the extent of absorption. The usual metrics for the absorption rate are the maximum measured plasma concentration (Cmax) and the time of maximum plasma concentration (Tmax). If absorption is ‘fast’, Cmax is high and Tmax is short. Conversely, if absorption is ‘slow’, Cmax is low and Tmax is long. Absorption rate may or may not be of clinical consequence depending on the nature of the drug and the circumstances of administration. High, early peaks may be desirable, for example, in the case of analgesic drug administration, when early onset of action is the objective, or unwanted when high, early peaks are associated with toxicity. The absorption rate often is of no clinical importance, as with drugs such as digoxin or warfarin [18]. Since few drugs are absorbed to a significant extent in the stomach, absorption rate is largely determined by how fast the ingested drug reaches absorptive surfaces in the proximal small bowel. Predictive scenarios can be constructed in which drug absorption rate might be increased, decreased, or unchanged in RYGB patients compared to non-surgical controls. The question of what constitutes appropriate controls remains a critical research issue. In any case, clinical studies variously show faster, slower, or unchanged drug absorption rates in RYGB patients, without validation of any specific predictive scheme. The extent of drug absorption—sometimes termed ‘absolute bioavailability’—refers to the fraction (F) of an orally administered dose that reaches the systemic circulation. Area under the plasma concentration–time curve (AUC) from time zero to infinity (AUC?) is related to F, but is not equivalent to F. The actual quantitative determination of F in an individual subject or patient requires two study trials: one in which AUC? is determined after oral dosage (AUCoral), and another in which AUC? is determined after intravenous administration of the same dose (AUCIV). F is calculated as: F ¼ ðAUCoral Þ=ðAUCIV Þ AUCoral is modified by clearance as well as the extent of absorption, and as such cannot be fully interpreted without the context of AUCIV Drugs are sometimes descriptively characterized as being ‘well absorbed’. This is not a quantitative term, and the specific meaning may not be evident. Use of the specific quantitative metrics of the rate and extent of absorption (as described above) is preferable. The loss of absorptive surface area following RYGB does not necessarily lead to a reduction in the extent of drug absorption. Even with reduced intestinal surface area, sufficient surface remains such that the extent of absorption may not be compromised. Therefore, the effect of the loss of surface area is best considered on a drug-by-drug basis, based on factors such as molecular size, polarity, acid–base
H. K. Greenblatt, D. J. Greenblatt
status, acid dissociation constant (pKa), and lipid solubility. A second consideration is the exposure to enzymes involved in enteric first-pass metabolism, such as cytochrome P450 (CYP) 3A. This would be expected to affect only drugs that ordinarily undergo enteric presystemic extraction. Increased pH in an RYGB gastric pouch compared with a normal stomach, due to reduced acid secretion, could affect pH-dependent drug absorption. The upregulation of certain enteric transport proteins after surgery has also been suggested [19]. These transporters may cause net movement of a molecule either into the circulation (uptake transport, as with fexofenadine) or back into the gastrointestinal tract lumen (efflux transport, as with digoxin). Whether RYGB significantly alters transporter expression or function is not clearly established, and in any case the net clinical effect would depend on the magnitude of the change and the characteristics of the specific drug. Ethanol absorption following RYGB merits particular attention. The rate of alcohol absorption is increased in gastric bypass patients compared with matched non-surgical controls [20, 21]. The consequence is higher peak blood alcohol concentrations occurring more rapidly after ingestion. It is possible that the higher, earlier blood ethanol peaks are associated with more intense subjective reinforcing effects. This might explain an increased incidence of alcohol abuse and dependence among postoperative patients, as reported in a number of studies [22–24].
4 Effect of Obesity and Weight Loss on Drug Disposition Drug distribution and drug clearance are separate and independent biomedical entities, regulated by separate and independent factors [11, 12]. Drug distribution—generally quantitated as a hypothetical apparent volume of distribution (Vd)—reflects the extent to which the drug distributes to tissues outside the vascular system [25, 26]. A drug’s lipid-solubility is a major determinant of its Vd, along with plasma protein binding and blood flow to individual body compartments. Drug clearance, on the other hand, has units of volume/time, and is the best single quantitative index of an individual’s capacity to clear or eliminate a specific drug. Clearance is independent of Vd, and is generally mediated by the liver (via metabolic biotransformation) or the kidney (via urinary excretion of the intact drug). Clearance—and not Vd—is the principal determinant of steady-state plasma concentrations of a drug during continuous treatment with a fixed daily dosage. Compared to ‘normal-weight’ controls, obese individuals have a higher total body weight and a different body composition. The weight in excess of ideal weight is
largely comprised of adipose tissue. For lipid-soluble drugs, obesity may cause a profound change in Vd, such that the increase in distribution is greatly disproportionate to the excess weight. For more water-soluble drugs, distribution in obese individuals remains restricted mainly to non-adipose tissues, and Vd may be minimally different from that in normal-weight controls [11, 12, 27]. As for drug clearance in obesity, clearance may or may not change in proportion to body weight, depending on the specific drug and its mechanism of clearance. The common comorbidity of obesity with type 2 diabetes raises the question of the contribution of diabetes as such to pharmacokinetic changes associated with obesity. Alterations in drug metabolism and transport have been reported in some experimental animal models of diabetes [28]. However, the consensus based on clinical studies is that alterations in metabolism and transport attributable to diabetes alone are not clearly evident, and not of established clinical importance [29]. Changes in drug distribution and clearance are anticipated as a result of significant weight loss following RYGB. Total body weight will be lower, and body composition (the percentage of adipose tissue versus lean mass) will also change. What remains unclear is whether body composition in patients now at normal weight following RYGB is comparable to normal-weight subjects who have never been obese. Yska et al. [30] also proposed that drug binding by a-1-acid glycoprotein (AAG) may be reduced following weight loss, causing changes in the extravascular distribution of drugs that are highly AAGbound. The extent to which weight loss in formerly obese individuals alters drug clearance is a critical issue in clinical therapeutics. Again it is not established whether clearance in post-RYGB patients is comparable to that in controls who have never been obese and have not had surgery. Intrinsic alterations in the activity of metabolic enzymes could change clearance of some drugs, as could hepatic blood flow. Reduced hepatic blood flow compared to lean control animals has been reported for genetically, obese Zucker rats [31], and for animals with diet-induced obesity [32]. It is not established whether this applies to humans, and whether weight loss would lead to normalization of hepatic blood flow. This could be of importance for orally administered drugs with high hepatic clearance and high extraction ratios. Finally, for drugs that undergo enteric first-pass metabolism, obesity can cause changes in the transcriptional regulation of enzymes such as uridine diphosphate (UDP)-glucuronosyltransferase (UGT). Xu et al. [33] reported an increase in UGT expression in hepatocytes of obese mice, likely mediated by increased activity of intracellular lipid-signalling pathways. If this also applies to humans, then obese individuals may have
Drug Disposition and Bariatric Surgery
increased UGT activity and increased clearance of drugs metabolized by UGTs. Clinical pharmacokinetic studies have demonstrated increased clearance of lorazepam, oxazepam, and acetaminophen—all of which are cleared by UGT-mediated biotransformation—in obese subjects [34, 35]. With weight loss, this increase might revert to normal, but this is not established.
5 Existing Evidence for Roux-en-Y Gastric Bypass-Associated Pharmacokinetic Changes Pharmacokinetic changes associated with RYGB and other bariatric procedures have been previously reviewed by a number of authors [2, 19, 30, 36–41]. The outcomes are variable, and in some instances the same original data have been interpreted differently by different authors. The general consensus is that bariatric surgery may increase, decrease, or leave unchanged the rate and/or extent of drug absorption, or the rate of drug clearance. No specific drug characteristics have been identified that provide predictive validity as to the effect of bariatric surgery on drug disposition. Much of the existing original data has significant limitations. Sample sizes often are small, between-subject variability may be large, and the selection of appropriate control groups for comparison is a concern. Many studies use a within-subject crossover design in which RYGB patients are studied prior to and again after surgery; other studies use matched cohort controls [42]. The pharmacokinetics of some drugs, such as metformin, have only been examined in a single study or by a single group of investigators. Metformin is an important example because of the prevalent use of oral antidiabetics in patients who undergo RYGB. Padwal et al. [43] reported that the plasma AUC? after oral metformin was increased by 20 % in RYGB patients in comparison with control subjects, but the difference was not significant. Five review articles discuss changes in metformin pharmacokinetics [2, 19, 38, 39, 41], and each cites the Padwal et al. [43] study as the supporting evidence. Among these reviews, there was inconsistent judgment as to whether the post-RYGB changes in the single metformin study reached statistical significance or clinical importance. The same kind of issue was applicable to the Rogers et al. [44] study on the immunosuppressant drug tacrolimus. Another major limitation is the inability of most original studies to separate surgical effects from weight-loss effects. This is discussed above. Most commonly, pharmacokinetics are evaluated in RYGB patients several months postoperatively when significant weight loss may have occurred. As such, pharmacokinetic changes could be due to the surgical procedure, to weight loss, or a combination of the two. A notable exception is a study by
Lloret-Linares et al. [45], which evaluated oral morphine pharmacokinetics prior to surgery, and at 15 days and 6 months postoperatively. Compared to AUC values before surgery, morphine AUC was increased at both postoperative times; however, the weight-normalized AUC (AUC 9 body weight) changed little between the three study conditions, suggesting that changes in oral clearance were explained by weight loss. The rate of morphine absorption was significantly increased at both postoperative times, as reflected by a shorter Tmax and higher Cmax. These findings indicate that both surgery and weight loss change morphine pharmacokinetics independently of one another. A final issue is the question of whether pharmacokinetic changes resulting from RYGB may be extrapolated to other bariatric procedures that are only restrictive or only malabsorptive. As discussed above, current trends indicate that RYGB is being supplanted by laparoscopic GB procedures. However, there is minimal research data on the effects of SG and other restrictive procedures on drug disposition.
6 Statistical Significance Versus Clinical Importance Clinical pharmacokinetic studies are generally designed to determine whether pharmacokinetic changes between two treatment conditions reach statistical significance; that is, whether they could have occurred by chance. A small change that is consistent in magnitude and direction between two conditions may reach statistical significance. For example, a drug’s clearance might change from 100 mL/ min prior to surgery to 90 mL/min two weeks after surgery. If the difference is consistent in this direction from patient to patient, it might well reach statistical significance, and one would conclude that bariatric surgery significantly impairs drug clearance. However, statistical significance is only one piece of the biomedical question—of equal or greater importance is whether the difference is meaningful in clinical practice. A reduction in clearance of 10 % implies that, at any given dosing rate, the steady-state blood concentration would change only by approximately 10 % in the other direction. Is this difference of clinical importance in terms of management of the patient’s underlying condition, or the susceptibility to adverse reactions? This question cannot be answered from pharmacokinetic data alone—it requires additional information on the concentration–response relationship for that particular drug. For most drugs, a 10 % difference in clearance is very unlikely to be of clinical importance. To this end, the outcome of each pharmacokinetic study needs to be interpreted in light of the concentration–response relationship for the substrate drug in question, and clinical conclusions need to be drawn accordingly.
H. K. Greenblatt, D. J. Greenblatt Table 1 Drugs and drug classes evaluated through controlled studies in patients who have undergone bariatric surgerya Central nervous system drugs
Analgesics
Antiinfective agents
Immunosupressants
Sertraline
Acetaminophen
Azithromycin
Tacrolimus
Metformin
Ranitidine
Digoxin
Hydrochlorothiazide
Venlafaxine
Morphine
Erythromycin
Sirolimus
Tolbutamide
Omeprazole
Atorvastatin
Oral contraceptives
Ampicillin Sulfisoxazole
Cyclosporine Mycophenolic acid
Propylthiouracil
Caffeine
Duloxetine Citalopram
Antidiabetic drugs
Anti-ulcer agents
Cardiovascular and metabolic drugs
Others
Escitalopram Haloperidol
Penicillin
Midazolam a
See references [2, 19, 38, 39, 41]
7 Conclusions and Recommendations Obesity is a major health problem in the Western world. Many patients with excess body weight are not able to cope with the problem through diet and exercise alone, and many elect to seek solutions through bariatric surgery aimed at reducing patterns of nutrient absorption, restricting the volume of meals, or some combination of the two. Many individuals with obesity have comorbid medical conditions, including type 2 diabetes, lipid disorders, and cardiovascular disease. The important question arises as to whether surgical procedures designed to modify body weight influence the pharmacokinetics or clinical effects of medications administered to such patients. Possible sources of pharmacokinetic modifications include changes in actual drug absorption due to altered surface area or transit time; changes in drug distribution due to alterations in body size and composition; and changes in metabolic activity (clearance) due to changes in enteric or hepatic drug-metabolizing capacity. Table 1 summarizes drugs and drug classes for which the influence of bariatric surgery on pharmacokinetic properties has been evaluated in controlled clinical studies. At present, there is no single unified model that can predict changes in drug distribution and clearance associated with either bariatric surgery or the weight loss that is likely to follow. Each drug or drug class stands as an individual entity that needs to be investigated as such. Factors likely to influence the outcome include the mechanism of drug absorption (passive diffusion versus uptake or efflux transport); the molecular size, charge, acid–base status, pKa, and lipid solubility of the drug in question; and the particular mechanism of drug clearance (enteric metabolism, hepatic metabolism, renal excretion). Research designs that consider changes in pharmacokinetics between the pre-surgical condition and the period following extensive weight loss do not necessarily allow resolution of the
mechanisms attributable to the surgery itself as opposed to the accompanying weight loss. As newer, less invasive approaches to bariatric surgery become increasingly common in clinical practice, the influence of these procedures on drug disposition needs to be addressed through systematically designed studies to resolve the effects of surgery from those of weight loss. Acknowledgments The authors have no conflicts of interest. There was no source of funding for the preparation of this article.
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LEADING ARTICLE
Altered Drug Disposition Following Bariatric Surgery: A Research Challenge H. Karl Greenblatt1 • David J. Greenblatt1
Ó Springer International Publishing Switzerland 2015
Abstract Bariatric surgery constitutes an approach to the management of obesity in which the anatomy of the gastrointestinal tract is altered to reduce access of nutrients to absorptive surfaces, to restrict the absolute volume of material that can be ingested at once, or a combination of the two. Roux-en-Y gastric bypass (RYGB), currently the most common bariatric surgical procedure worldwide, has both malabsorptive and restrictive features. RYGB can be associated with alterations in absorption and disposition of medications. However documenting and predicting the specific pharmacokinetic changes associated with RYGB is a difficult research challenge. Because obesity and weight loss themselves can alter drug disposition, it may be difficult or impossible to resolve whether pharmacokinetic alterations in post-RYGB patients are due to the surgery itself as opposed to the subsequent weight loss. Changes in disposition of medications may be drug-specific as opposed to generalized. Further, statistically significant modifications in drug disposition are not necessarily of clinical importance. Clinical decisions on medication use in postbariatric surgical patients should be based on a review of the original literature dealing with the particular drug in question.
& David J. Greenblatt [email protected] 1
Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
Key Points Alterations in drug disposition in post-bariatric surgical patients can be due to a combination of altered gastrointestinal tract anatomy and physiology, together with the effects of subsequent weight loss. No valid paradigm is available to predict the specific changes in drug absorption and clearance associated with bariatric surgery, the magnitude of the changes, and whether they are clinically important. Clinical decisions on medication use in these patients should be based on a review of the original literature dealing with the particular drug in question.
1 Introduction Obesity is a significant worldwide public health concern [1]. As of 2008, approximately one-third of the US population was considered obese, with a body mass index (BMI) of 30 kg/m2 or higher [2, 3]. In obese patients, the most common comorbid conditions include glucose intolerance and type 2 diabetes, hypertension, lipid disorders, coronary artery disease, and joint damage. The most recent US data from the National Health and Nutrition Examination Survey indicate that the prevalence of obesity has stabilized over the last 10 years [3]. This is an encouraging trend, but obesity nonetheless continues to be a public health problem of high prevalence (Fig. 1).
H. K. Greenblatt, D. J. Greenblatt
Fig. 1 Fraction of the adult American population with body mass index (BMI) values exceeding 30, 35 and 40 kg/m2. The data are from the 2011–2012 National Health and Nutrition Examination Survey [3]
Bariatric surgery is an available option for obese individuals to achieve and sustain weight loss [4–6]. The estimated number of bariatric procedures performed worldwide increased from 146,000 in 2003 to about 344,000 in 2008 [4, 7, 8]. The numbers were nearly identical in 2011. A similar trend was seen in North America between 2003 and 2008 (from 103,000 up to 220,000). However, by 2011, the number had decreased dramatically to 102,000. Also evident are changes over time in the types of procedure performed [4, 7, 8]. The Roux-en-Y gastric bypass (RYGB) remains the most common procedure worldwide, though its use in the USA has declined considerably since 2008. Adjustable gastric banding (AGB) is also diminishing in popularity, and procedures such as biliopancreatic diversion/duodenal switch, mini gastric bypass, and vertical banded gastroplasty are done uncommonly. Sleeve gastrectomy (SG) has rapidly increased in popularity, going from 18,000 procedures worldwide in 2008 to 95,000 in 2011. A general trend to laparoscopic approaches is observed overall, probably because of the lower level of invasiveness, accelerated recovery, reduction in complications, and reduced postoperative pain. Bariatric surgical procedures are generally classified as either restrictive or malabsorptive [4–6]. Restrictive procedures reduce the volume of the stomach, thereby limiting the net volume that an individual can ingest at one time. Malabsorptive procedures reduce the available intestinal surface area, thereby reducing the net area available for drug and nutrient absorption. RYGB—still the most common of the bariatric procedures—is both restrictive and malabsorptive; the small intestine is reconnected to a 30–60 mL gastric pouch, bypassing the duodenum, jejunum, and most
of the ileum. RYGB leaves the patient with a substantially reduced absorptive surface area. The effectiveness of RYGB in producing weight loss has been demonstrated repeatedly [9, 10]. In a review of available clinical trials, Chang et al. [10] reported a mean loss of 41–62 % of excess weight at 5 years after surgery. It is not surprising that an anticipated complication of RYGB is malabsorption of nutrients and vitamins. A parallel concern is the possibility that RYGB, independently of whether weight loss occurs, alters the absorption, distribution, and clearance of drugs. Obesity and surgery both predispose individuals to comorbidities that require pharmacological management, so any changes in drug metabolism and disposition might disproportionately affect outcomes in RYGB patients. The purpose of this article is to examine the evidence for pharmacokinetic alterations associated with bariatric surgery, and whether such changes, if they occur, are of clinical or therapeutic importance. Most of the available research data relates to RYGB and other predominantly malabsorptive procedures. Given the emergent popularity of predominantly restrictive procedures such as laparoscopic SG, there is a need for data on drug disposition changes associated with this category of bariatric surgery.
2 Drug Disposition Following Bariatric Surgery: Framing the Research Questions The physiological bases for post-RYGB changes in the pharmacokinetic behaviour of drugs can be categorized as those resulting from the procedure itself, and those that stem from subsequent weight loss. In principle, these are distinct and independent, though they generally co-exist in bariatric surgery patients. Resolution of the separate underlying mechanism for pharmacokinetic changes, and ultimately understanding the net clinical and therapeutic implications, requires close attention to the research questions and to the construction of research designs. There is extensive research data available on the effects of obesity on drug distribution and clearance [11–17]. Nearly all of this work is based on comparisons of cohorts of obese individuals with parallel cohorts of ‘normalweight’ controls, often matched according to age and gender. Generally the control population in cohort studies of this type has never been significantly obese, and has not experienced extensive weight loss. These cohort comparisons do not constitute studies of weight loss, in which drug disposition is evaluated in the same individual first during obesity, and again after weight loss. It cannot be assumed that features of body composition and drug disposition are identical between individuals who were formerly obese before becoming ‘normal’ in body weight, as opposed to
Drug Disposition and Bariatric Surgery
subjects who were never obese. Ironically, nearly all studies of drug disposition following weight loss involve individuals who have had bariatric surgery, thereby thwarting the objective of resolving the effects of surgery from those of weight loss. Similar methodological problems complicate study of the pharmacokinetic consequences of the surgical procedure itself, independent of weight loss. RYGB creates a small gastric pouch (reduction in stomach volume), and loss of functional intestinal surface area—changes likely to be permanent. In principle, these anatomical changes could affect the rate and extent of drug absorption, enteric metabolism, enteric efflux transport, hepatic presystemic extraction, and net hepatic clearance. Oral and/or parenteral drug disposition could be studied in the same individuals before and shortly after bariatric surgery, but this is a study of surgical effects in patients who are still obese. If enough time passes to allow significant weight loss, the study becomes an evaluation of surgery plus weight loss. A cohort study of post-surgical patients who have attained normal weight compared to never-obese non-surgical controls still has the potential confounding problem described above. RYGB surgery for indications other than obesity is likely to be rare, so there is a low probability of encountering post-RYGB patients who have not undergone weight loss. In the context of bariatric surgery, the physiological and pharmacokinetic consequences of the surgical procedure itself are necessarily mingled with the consequences of obesity and of weight loss. A combination of longitudinal and cohort designs probably constitutes the most reasonable overall research strategy. For the longitudinal component, the kinetics of the target drug are determined in the same individual first prior to surgery, again in the proximal postoperative period before significant weight loss has occurred, and finally after time has elapsed and body weight has been reduced. The cohort component would involve study of post-surgical patients who have attained ‘normal’ weight compared to individuals of comparable body weight and habitus who have not had surgery, have never been obese, and have not lost weight.
3 Enteric Anatomy and Physiology Following Roux-en-Y Gastric Bypass Surgery It could be speculated that RYGB would decrease the absorption of all drugs simply through loss of surface area. However the determinants of drug absorption are complex, and the straightforward assumption is not generally valid. The rate and extent of drug absorption are independent and not necessarily related [18]. Absorption rate relates to how fast a drug reaches the systemic circulation after oral
administration, regardless of the extent of absorption. The usual metrics for the absorption rate are the maximum measured plasma concentration (Cmax) and the time of maximum plasma concentration (Tmax). If absorption is ‘fast’, Cmax is high and Tmax is short. Conversely, if absorption is ‘slow’, Cmax is low and Tmax is long. Absorption rate may or may not be of clinical consequence depending on the nature of the drug and the circumstances of administration. High, early peaks may be desirable, for example, in the case of analgesic drug administration, when early onset of action is the objective, or unwanted when high, early peaks are associated with toxicity. The absorption rate often is of no clinical importance, as with drugs such as digoxin or warfarin [18]. Since few drugs are absorbed to a significant extent in the stomach, absorption rate is largely determined by how fast the ingested drug reaches absorptive surfaces in the proximal small bowel. Predictive scenarios can be constructed in which drug absorption rate might be increased, decreased, or unchanged in RYGB patients compared to non-surgical controls. The question of what constitutes appropriate controls remains a critical research issue. In any case, clinical studies variously show faster, slower, or unchanged drug absorption rates in RYGB patients, without validation of any specific predictive scheme. The extent of drug absorption—sometimes termed ‘absolute bioavailability’—refers to the fraction (F) of an orally administered dose that reaches the systemic circulation. Area under the plasma concentration–time curve (AUC) from time zero to infinity (AUC?) is related to F, but is not equivalent to F. The actual quantitative determination of F in an individual subject or patient requires two study trials: one in which AUC? is determined after oral dosage (AUCoral), and another in which AUC? is determined after intravenous administration of the same dose (AUCIV). F is calculated as: F ¼ ðAUCoral Þ=ðAUCIV Þ AUCoral is modified by clearance as well as the extent of absorption, and as such cannot be fully interpreted without the context of AUCIV Drugs are sometimes descriptively characterized as being ‘well absorbed’. This is not a quantitative term, and the specific meaning may not be evident. Use of the specific quantitative metrics of the rate and extent of absorption (as described above) is preferable. The loss of absorptive surface area following RYGB does not necessarily lead to a reduction in the extent of drug absorption. Even with reduced intestinal surface area, sufficient surface remains such that the extent of absorption may not be compromised. Therefore, the effect of the loss of surface area is best considered on a drug-by-drug basis, based on factors such as molecular size, polarity, acid–base
H. K. Greenblatt, D. J. Greenblatt
status, acid dissociation constant (pKa), and lipid solubility. A second consideration is the exposure to enzymes involved in enteric first-pass metabolism, such as cytochrome P450 (CYP) 3A. This would be expected to affect only drugs that ordinarily undergo enteric presystemic extraction. Increased pH in an RYGB gastric pouch compared with a normal stomach, due to reduced acid secretion, could affect pH-dependent drug absorption. The upregulation of certain enteric transport proteins after surgery has also been suggested [19]. These transporters may cause net movement of a molecule either into the circulation (uptake transport, as with fexofenadine) or back into the gastrointestinal tract lumen (efflux transport, as with digoxin). Whether RYGB significantly alters transporter expression or function is not clearly established, and in any case the net clinical effect would depend on the magnitude of the change and the characteristics of the specific drug. Ethanol absorption following RYGB merits particular attention. The rate of alcohol absorption is increased in gastric bypass patients compared with matched non-surgical controls [20, 21]. The consequence is higher peak blood alcohol concentrations occurring more rapidly after ingestion. It is possible that the higher, earlier blood ethanol peaks are associated with more intense subjective reinforcing effects. This might explain an increased incidence of alcohol abuse and dependence among postoperative patients, as reported in a number of studies [22–24].
4 Effect of Obesity and Weight Loss on Drug Disposition Drug distribution and drug clearance are separate and independent biomedical entities, regulated by separate and independent factors [11, 12]. Drug distribution—generally quantitated as a hypothetical apparent volume of distribution (Vd)—reflects the extent to which the drug distributes to tissues outside the vascular system [25, 26]. A drug’s lipid-solubility is a major determinant of its Vd, along with plasma protein binding and blood flow to individual body compartments. Drug clearance, on the other hand, has units of volume/time, and is the best single quantitative index of an individual’s capacity to clear or eliminate a specific drug. Clearance is independent of Vd, and is generally mediated by the liver (via metabolic biotransformation) or the kidney (via urinary excretion of the intact drug). Clearance—and not Vd—is the principal determinant of steady-state plasma concentrations of a drug during continuous treatment with a fixed daily dosage. Compared to ‘normal-weight’ controls, obese individuals have a higher total body weight and a different body composition. The weight in excess of ideal weight is
largely comprised of adipose tissue. For lipid-soluble drugs, obesity may cause a profound change in Vd, such that the increase in distribution is greatly disproportionate to the excess weight. For more water-soluble drugs, distribution in obese individuals remains restricted mainly to non-adipose tissues, and Vd may be minimally different from that in normal-weight controls [11, 12, 27]. As for drug clearance in obesity, clearance may or may not change in proportion to body weight, depending on the specific drug and its mechanism of clearance. The common comorbidity of obesity with type 2 diabetes raises the question of the contribution of diabetes as such to pharmacokinetic changes associated with obesity. Alterations in drug metabolism and transport have been reported in some experimental animal models of diabetes [28]. However, the consensus based on clinical studies is that alterations in metabolism and transport attributable to diabetes alone are not clearly evident, and not of established clinical importance [29]. Changes in drug distribution and clearance are anticipated as a result of significant weight loss following RYGB. Total body weight will be lower, and body composition (the percentage of adipose tissue versus lean mass) will also change. What remains unclear is whether body composition in patients now at normal weight following RYGB is comparable to normal-weight subjects who have never been obese. Yska et al. [30] also proposed that drug binding by a-1-acid glycoprotein (AAG) may be reduced following weight loss, causing changes in the extravascular distribution of drugs that are highly AAGbound. The extent to which weight loss in formerly obese individuals alters drug clearance is a critical issue in clinical therapeutics. Again it is not established whether clearance in post-RYGB patients is comparable to that in controls who have never been obese and have not had surgery. Intrinsic alterations in the activity of metabolic enzymes could change clearance of some drugs, as could hepatic blood flow. Reduced hepatic blood flow compared to lean control animals has been reported for genetically, obese Zucker rats [31], and for animals with diet-induced obesity [32]. It is not established whether this applies to humans, and whether weight loss would lead to normalization of hepatic blood flow. This could be of importance for orally administered drugs with high hepatic clearance and high extraction ratios. Finally, for drugs that undergo enteric first-pass metabolism, obesity can cause changes in the transcriptional regulation of enzymes such as uridine diphosphate (UDP)-glucuronosyltransferase (UGT). Xu et al. [33] reported an increase in UGT expression in hepatocytes of obese mice, likely mediated by increased activity of intracellular lipid-signalling pathways. If this also applies to humans, then obese individuals may have
Drug Disposition and Bariatric Surgery
increased UGT activity and increased clearance of drugs metabolized by UGTs. Clinical pharmacokinetic studies have demonstrated increased clearance of lorazepam, oxazepam, and acetaminophen—all of which are cleared by UGT-mediated biotransformation—in obese subjects [34, 35]. With weight loss, this increase might revert to normal, but this is not established.
5 Existing Evidence for Roux-en-Y Gastric Bypass-Associated Pharmacokinetic Changes Pharmacokinetic changes associated with RYGB and other bariatric procedures have been previously reviewed by a number of authors [2, 19, 30, 36–41]. The outcomes are variable, and in some instances the same original data have been interpreted differently by different authors. The general consensus is that bariatric surgery may increase, decrease, or leave unchanged the rate and/or extent of drug absorption, or the rate of drug clearance. No specific drug characteristics have been identified that provide predictive validity as to the effect of bariatric surgery on drug disposition. Much of the existing original data has significant limitations. Sample sizes often are small, between-subject variability may be large, and the selection of appropriate control groups for comparison is a concern. Many studies use a within-subject crossover design in which RYGB patients are studied prior to and again after surgery; other studies use matched cohort controls [42]. The pharmacokinetics of some drugs, such as metformin, have only been examined in a single study or by a single group of investigators. Metformin is an important example because of the prevalent use of oral antidiabetics in patients who undergo RYGB. Padwal et al. [43] reported that the plasma AUC? after oral metformin was increased by 20 % in RYGB patients in comparison with control subjects, but the difference was not significant. Five review articles discuss changes in metformin pharmacokinetics [2, 19, 38, 39, 41], and each cites the Padwal et al. [43] study as the supporting evidence. Among these reviews, there was inconsistent judgment as to whether the post-RYGB changes in the single metformin study reached statistical significance or clinical importance. The same kind of issue was applicable to the Rogers et al. [44] study on the immunosuppressant drug tacrolimus. Another major limitation is the inability of most original studies to separate surgical effects from weight-loss effects. This is discussed above. Most commonly, pharmacokinetics are evaluated in RYGB patients several months postoperatively when significant weight loss may have occurred. As such, pharmacokinetic changes could be due to the surgical procedure, to weight loss, or a combination of the two. A notable exception is a study by
Lloret-Linares et al. [45], which evaluated oral morphine pharmacokinetics prior to surgery, and at 15 days and 6 months postoperatively. Compared to AUC values before surgery, morphine AUC was increased at both postoperative times; however, the weight-normalized AUC (AUC 9 body weight) changed little between the three study conditions, suggesting that changes in oral clearance were explained by weight loss. The rate of morphine absorption was significantly increased at both postoperative times, as reflected by a shorter Tmax and higher Cmax. These findings indicate that both surgery and weight loss change morphine pharmacokinetics independently of one another. A final issue is the question of whether pharmacokinetic changes resulting from RYGB may be extrapolated to other bariatric procedures that are only restrictive or only malabsorptive. As discussed above, current trends indicate that RYGB is being supplanted by laparoscopic GB procedures. However, there is minimal research data on the effects of SG and other restrictive procedures on drug disposition.
6 Statistical Significance Versus Clinical Importance Clinical pharmacokinetic studies are generally designed to determine whether pharmacokinetic changes between two treatment conditions reach statistical significance; that is, whether they could have occurred by chance. A small change that is consistent in magnitude and direction between two conditions may reach statistical significance. For example, a drug’s clearance might change from 100 mL/ min prior to surgery to 90 mL/min two weeks after surgery. If the difference is consistent in this direction from patient to patient, it might well reach statistical significance, and one would conclude that bariatric surgery significantly impairs drug clearance. However, statistical significance is only one piece of the biomedical question—of equal or greater importance is whether the difference is meaningful in clinical practice. A reduction in clearance of 10 % implies that, at any given dosing rate, the steady-state blood concentration would change only by approximately 10 % in the other direction. Is this difference of clinical importance in terms of management of the patient’s underlying condition, or the susceptibility to adverse reactions? This question cannot be answered from pharmacokinetic data alone—it requires additional information on the concentration–response relationship for that particular drug. For most drugs, a 10 % difference in clearance is very unlikely to be of clinical importance. To this end, the outcome of each pharmacokinetic study needs to be interpreted in light of the concentration–response relationship for the substrate drug in question, and clinical conclusions need to be drawn accordingly.
H. K. Greenblatt, D. J. Greenblatt Table 1 Drugs and drug classes evaluated through controlled studies in patients who have undergone bariatric surgerya Central nervous system drugs
Analgesics
Antiinfective agents
Immunosupressants
Sertraline
Acetaminophen
Azithromycin
Tacrolimus
Metformin
Ranitidine
Digoxin
Hydrochlorothiazide
Venlafaxine
Morphine
Erythromycin
Sirolimus
Tolbutamide
Omeprazole
Atorvastatin
Oral contraceptives
Ampicillin Sulfisoxazole
Cyclosporine Mycophenolic acid
Propylthiouracil
Caffeine
Duloxetine Citalopram
Antidiabetic drugs
Anti-ulcer agents
Cardiovascular and metabolic drugs
Others
Escitalopram Haloperidol
Penicillin
Midazolam a
See references [2, 19, 38, 39, 41]
7 Conclusions and Recommendations Obesity is a major health problem in the Western world. Many patients with excess body weight are not able to cope with the problem through diet and exercise alone, and many elect to seek solutions through bariatric surgery aimed at reducing patterns of nutrient absorption, restricting the volume of meals, or some combination of the two. Many individuals with obesity have comorbid medical conditions, including type 2 diabetes, lipid disorders, and cardiovascular disease. The important question arises as to whether surgical procedures designed to modify body weight influence the pharmacokinetics or clinical effects of medications administered to such patients. Possible sources of pharmacokinetic modifications include changes in actual drug absorption due to altered surface area or transit time; changes in drug distribution due to alterations in body size and composition; and changes in metabolic activity (clearance) due to changes in enteric or hepatic drug-metabolizing capacity. Table 1 summarizes drugs and drug classes for which the influence of bariatric surgery on pharmacokinetic properties has been evaluated in controlled clinical studies. At present, there is no single unified model that can predict changes in drug distribution and clearance associated with either bariatric surgery or the weight loss that is likely to follow. Each drug or drug class stands as an individual entity that needs to be investigated as such. Factors likely to influence the outcome include the mechanism of drug absorption (passive diffusion versus uptake or efflux transport); the molecular size, charge, acid–base status, pKa, and lipid solubility of the drug in question; and the particular mechanism of drug clearance (enteric metabolism, hepatic metabolism, renal excretion). Research designs that consider changes in pharmacokinetics between the pre-surgical condition and the period following extensive weight loss do not necessarily allow resolution of the
mechanisms attributable to the surgery itself as opposed to the accompanying weight loss. As newer, less invasive approaches to bariatric surgery become increasingly common in clinical practice, the influence of these procedures on drug disposition needs to be addressed through systematically designed studies to resolve the effects of surgery from those of weight loss. Acknowledgments The authors have no conflicts of interest. There was no source of funding for the preparation of this article.
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