DRUG CONCENTRATION MONITORING
Clin. Pharmacokinet. 23 (5): 365-379, 1992 0312-5963/92/00 10-0365/$07.50/0 © Adis International Limited. All rights reserved. CPK1230
Therapeutic Drug Monitoring in Saliva An Update Robert K. Drobitch and Craig K. Svensson Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, Michigan, USA
Contents 365 366 366 367 368 368 369 370 37 J 37 J 37 J 374 375 375 376
Summary
Summary 1. Anatomy and Physiology of Saliva and the Salivary Glands 1.1 Composition of Saliva 1.2 Neural Control of Salivary Secretion 1.3 Effects of Disease and Drugs on Salivary Composition and Secretion 2. Determinants of Salivary Drug Concentration 2.1 Criteria for Selecting Drugs for Saliva Monitoring 2.2 Collection of Saliva 3. Evaluation of Specific Agents 3.1 Drug Evaluation and Literature Search Criteria 3.2 Anticonvulsants 3.3 Antiarrhythmics 3.4 Antidepressants 3.5 Miscellaneous Drugs 4. Conclusion
This article re-examines the issue of salivary therapeutic drug monitoring (STDM). The anatomy and physiology of saliva and the salivary glands, as well as the effects of disease and drugs on salivary secretion and composition, are discussed briefly. Drugs for which therapeutic drug monitoring (TDM) has been shown useful are individually considered to determine if salivary drug concentrations (Csal) are reflective of plasma free drug concentrations (Cup). That is, is the Csal/Cup ratio time- and concentration-independent, as supported by a review of literature data? The primary determinant which appears to govern the potential utility of STDM for many of the drugs is the pKa of the drug. Drugs which are not ionisable or are un-ionised within the salivary pH range (phenytoin, carbamazepine, theophylline) are candidates for STDM based on current literature data. Digoxin and cyclosporin are potential candidates for STDM; however, further studies are necessary to confirm these preliminary findings. On the basis of current literature data, STDM does not appear to be useful for other drugs therapeutically monitored in serum/plasma.
366
The use of drug concentration determinations to guide the individualisation of pharmacotherapy has gained widespread acceptance in a variety of clinical settings. The rational use of such determinations can provide a knowledge of patientspecific pharmacokinetic parameters leading to improved therapy (Spector et al. 1988). The use of drugs in prophylactic therapy may also prove to be an area where concentration determinations would provide useful assistance in clinical decisionmaking. Numerous investigators have suggested that saliva, which may be collected with minimal patient discomfort, can serve as a viable body fluid for therapeutic drug monitoring (TDM). However, it appears that this noninvasive method ofTDM has gained little acceptance in clinical practice (Danhof & Breimer 1978; Dvorchik & Vesell 1976; Haeckel 1989a; Homing et al. 1977). While the reasons for this lack of acceptance are surely multiple, a significant cause may be the inconsistent conclusions reached by investigators examining the potential of salivary therapeutic drug monitoring (STDM). We believe that much of this inconsistency is secondary to a lack of rigorous investigative methods used in many published studies. The present article reexamines the issue of STOM in an attempt to provide a critical review of our current knowledge and, in light of the criteria established, evaluate drugs for which STOM may serve as a viable alternative to plasma/serum concentration monitoring. Several recent developments provide a renewed impetus for STOM. First, the increased prevalence of individuals infected with the human immunodeficiency virus has led to heightened concerns regarding the risk associated with accidental needlestick injuries (Allen et al. 1991; Bailey 1990). Monitoring modalities that minimise the likelihood of these injuries would be welcome by a wide spectrum of health professionals. Secondly, over the past decade there has been an increased emphasis on free drug concentration determinations. For some drugs, saliva concentration determinations may provide a less expensive and less labourintensive means of estimating free drug concentrations. Thirdly, several simplified, self-contained
Clin. Pharmacokinet. 23 (5) 1992
methods for drug concentration determinations have been marketed which afford the potential for therapeutic drug monitoring in settings unaffiliated with laboratories (e.g. physicians' offices, community pharmacies). The use of saliva may provide a simple means to apply these methods to free concentration determinations for selected drugs.
1. Anatomy and Physiology of Saliva and the Salivary Glands Saliva is secreted by the 3 major paired salivary glands (parotid, sublingual and submaxillary) with the parotid and submaxillary glands accounting for 90% of the volume of secreted saliva under resting conditions (Jacobson 1981). Secretions of the parotid glands are watery and contain salivary amylase, an enzyme catalysing starch breakdown. Saliva secreted by the sublingual and submaxillary glands is mixed serous and mucoid due to the presence of mucous and serous cells within these glands (Jacobson 1981). The blood supply to the glands is provided by the external carotid artery with the direction of the arterial blood flow being countercurrent to the direction of salivary flow within the ductal system. Sympathetic and parasympathetic stimulation controls blood flow as well as glandular activity. 1.1 Composition of Saliva The composition of saliva (compared with plasma) in normal adults is summarised in table I (after Mandel 1974). As the composition of fluids secreted by the different salivary glands can be affected by a number of factors, including the time of day, diet, age, sex and changes in flow rate, the table provides a means of comparing saliva and plasma under the conditions described (Mandel 1974). Approximately 1200ml of saliva is secreted each day and it contains electrolytes common to the extracellular fluid, including sodium, potassium, chloride and bicarbonate, as well as protein and other substances present in smaller amounts. Saliva pH can range from 6.2 to 7.4, with the higher pH exhibited upon increased secretion due to an
367
Therapeutic Drug Monitoring in Saliva
Table I. Mean values of salivary composition in healthy adults compared with plasma. Saliva samples were obtained after stimulation with 2% citric acid (after Mandel 1974)
Specimen
Potassium b Sodium b Chloride b Bicarbonateb Calcium b Magnesium b Phosphate b Ureac Ammoniac Uric acid c Glucosec Totallipid c Cholesterolc Fatty acidsc Amino acidsc Proteinsc
pH a b c
Parotid saliva
Submaxillary saliva
(0.7 ml/min)8
(0.6 ml/min)8
20.0 23.0 23.0 20.0 2.0 0.2 6.0 15.0 0.3 3.0
Clin. Pharmacokinet. 23 (5): 365-379, 1992 0312-5963/92/00 10-0365/$07.50/0 © Adis International Limited. All rights reserved. CPK1230
Therapeutic Drug Monitoring in Saliva An Update Robert K. Drobitch and Craig K. Svensson Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, Michigan, USA
Contents 365 366 366 367 368 368 369 370 37 J 37 J 37 J 374 375 375 376
Summary
Summary 1. Anatomy and Physiology of Saliva and the Salivary Glands 1.1 Composition of Saliva 1.2 Neural Control of Salivary Secretion 1.3 Effects of Disease and Drugs on Salivary Composition and Secretion 2. Determinants of Salivary Drug Concentration 2.1 Criteria for Selecting Drugs for Saliva Monitoring 2.2 Collection of Saliva 3. Evaluation of Specific Agents 3.1 Drug Evaluation and Literature Search Criteria 3.2 Anticonvulsants 3.3 Antiarrhythmics 3.4 Antidepressants 3.5 Miscellaneous Drugs 4. Conclusion
This article re-examines the issue of salivary therapeutic drug monitoring (STDM). The anatomy and physiology of saliva and the salivary glands, as well as the effects of disease and drugs on salivary secretion and composition, are discussed briefly. Drugs for which therapeutic drug monitoring (TDM) has been shown useful are individually considered to determine if salivary drug concentrations (Csal) are reflective of plasma free drug concentrations (Cup). That is, is the Csal/Cup ratio time- and concentration-independent, as supported by a review of literature data? The primary determinant which appears to govern the potential utility of STDM for many of the drugs is the pKa of the drug. Drugs which are not ionisable or are un-ionised within the salivary pH range (phenytoin, carbamazepine, theophylline) are candidates for STDM based on current literature data. Digoxin and cyclosporin are potential candidates for STDM; however, further studies are necessary to confirm these preliminary findings. On the basis of current literature data, STDM does not appear to be useful for other drugs therapeutically monitored in serum/plasma.
366
The use of drug concentration determinations to guide the individualisation of pharmacotherapy has gained widespread acceptance in a variety of clinical settings. The rational use of such determinations can provide a knowledge of patientspecific pharmacokinetic parameters leading to improved therapy (Spector et al. 1988). The use of drugs in prophylactic therapy may also prove to be an area where concentration determinations would provide useful assistance in clinical decisionmaking. Numerous investigators have suggested that saliva, which may be collected with minimal patient discomfort, can serve as a viable body fluid for therapeutic drug monitoring (TDM). However, it appears that this noninvasive method ofTDM has gained little acceptance in clinical practice (Danhof & Breimer 1978; Dvorchik & Vesell 1976; Haeckel 1989a; Homing et al. 1977). While the reasons for this lack of acceptance are surely multiple, a significant cause may be the inconsistent conclusions reached by investigators examining the potential of salivary therapeutic drug monitoring (STDM). We believe that much of this inconsistency is secondary to a lack of rigorous investigative methods used in many published studies. The present article reexamines the issue of STOM in an attempt to provide a critical review of our current knowledge and, in light of the criteria established, evaluate drugs for which STOM may serve as a viable alternative to plasma/serum concentration monitoring. Several recent developments provide a renewed impetus for STOM. First, the increased prevalence of individuals infected with the human immunodeficiency virus has led to heightened concerns regarding the risk associated with accidental needlestick injuries (Allen et al. 1991; Bailey 1990). Monitoring modalities that minimise the likelihood of these injuries would be welcome by a wide spectrum of health professionals. Secondly, over the past decade there has been an increased emphasis on free drug concentration determinations. For some drugs, saliva concentration determinations may provide a less expensive and less labourintensive means of estimating free drug concentrations. Thirdly, several simplified, self-contained
Clin. Pharmacokinet. 23 (5) 1992
methods for drug concentration determinations have been marketed which afford the potential for therapeutic drug monitoring in settings unaffiliated with laboratories (e.g. physicians' offices, community pharmacies). The use of saliva may provide a simple means to apply these methods to free concentration determinations for selected drugs.
1. Anatomy and Physiology of Saliva and the Salivary Glands Saliva is secreted by the 3 major paired salivary glands (parotid, sublingual and submaxillary) with the parotid and submaxillary glands accounting for 90% of the volume of secreted saliva under resting conditions (Jacobson 1981). Secretions of the parotid glands are watery and contain salivary amylase, an enzyme catalysing starch breakdown. Saliva secreted by the sublingual and submaxillary glands is mixed serous and mucoid due to the presence of mucous and serous cells within these glands (Jacobson 1981). The blood supply to the glands is provided by the external carotid artery with the direction of the arterial blood flow being countercurrent to the direction of salivary flow within the ductal system. Sympathetic and parasympathetic stimulation controls blood flow as well as glandular activity. 1.1 Composition of Saliva The composition of saliva (compared with plasma) in normal adults is summarised in table I (after Mandel 1974). As the composition of fluids secreted by the different salivary glands can be affected by a number of factors, including the time of day, diet, age, sex and changes in flow rate, the table provides a means of comparing saliva and plasma under the conditions described (Mandel 1974). Approximately 1200ml of saliva is secreted each day and it contains electrolytes common to the extracellular fluid, including sodium, potassium, chloride and bicarbonate, as well as protein and other substances present in smaller amounts. Saliva pH can range from 6.2 to 7.4, with the higher pH exhibited upon increased secretion due to an
367
Therapeutic Drug Monitoring in Saliva
Table I. Mean values of salivary composition in healthy adults compared with plasma. Saliva samples were obtained after stimulation with 2% citric acid (after Mandel 1974)
Specimen
Potassium b Sodium b Chloride b Bicarbonateb Calcium b Magnesium b Phosphate b Ureac Ammoniac Uric acid c Glucosec Totallipid c Cholesterolc Fatty acidsc Amino acidsc Proteinsc
pH a b c
Parotid saliva
Submaxillary saliva
(0.7 ml/min)8
(0.6 ml/min)8
20.0 23.0 23.0 20.0 2.0 0.2 6.0 15.0 0.3 3.0
