Lockwood and Peters
6.
7.
8.
9. 10.
bryonic and adult human tissues.] Cell Sci 1987;88:41930. Peters ]H, Maunder R, Woolf A, Cochrane CG, Ginsberg MH. Elevated plasma levels of ED 1 + ("cellular") fibronectin in patients with vascular injury. ] Lab Clin Med 1989; 113 :586-97. Lazarchick], Stubbs TM, Romein L. Predictive value of fibronectin levels in normotensive gravid women destined to become preeclamptic. AM] OBSTET GYNECOL 1986; 154: 1050-2. Stubbs TM, Lazarchick], Horger EO. Plasma fibronectin levels in preeclampsia: a possible biochemical marker for vascular endothelial damage. AM ] OBSTET GYNECOL 1984;150:885-7. Saleh AA, Bottoms SF, Welch RA, et al. Preeclampsia, delivery, and the hemostatic system. AM ] OBSTET GyNECOL 1987;157:331-5. Peters ]H, Ginsberg MH, Case CM, Cochrane CH. Release of soluble fibronectin containing an extra type III domain (ED1) during acute pulmonary injury mediated by oxidants or leukocytes in vivo. Am Rev Respir Dis 1988; 138: 167-74.
February 1990 Am J Obstet Gynecol
11. Peters ]H, Ginsberg MH, Bohl BP, Sklar LA, Cochrane CG. Intravascular release of intact cellular fibronectin during oxidant-induced injury of the in vitro perfused rabbit lung.] Clin Invest 1986;78:1596-603. 12. Rodgers GM, Taylor RN, Roberts ]M. Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells. AM] OBSTET GYNECOL 1988;159:908-14. 13. Annunciado AN, Stubbs TM, Pepkowitz SH, et al. Altered villus vessel fibronectin in preeclampsia. AM ] 08STET GYNECOL 1987; 156:898-900. 14. Paul]I, Schwarzbauer ]E, Tamkun]W, Hynes RO. Celltype specific fibronectin subunits generated by alternative splicing. ] Bioi Chern 1986;261: 12258-65. 15. Pick-Kober KH, Munker D, Gressner AM. Fibronectin is synthesized as an acute phase reactant in rat hepatocytes. ] Clin Chern Clin Biochem 1986;24:521-8. 16. Cosio FG, Bakaletz AP. Abnormal plasma fibronectin levels in patients with proteinuria. ] Lab Clin Med 1984; 104:863.
Labetalol pharmacokinetics in pregnancy-induced hypertension Rebecca C. Rogers, PharrnD, Baha M. Sibai, MD, and W. David Whybrew, MS Memphis, Tennessee Pharmacokinetic parameters of oral labetalol were studied in eight women with pregnancy-induced hypertension in the third trimester of pregnancy. Labetalol exhibited rapid absorption; peak serum concentrations of 881 ± 219 ng/ml occurred at 20 minutes after labetalol ingestion. The terminal elimination half-life (mean, 1.7 ± 0.27 hours) was found to be shorter than that reported for normotensive volunteers or nonpregnant hypertensive patients (mean, 6 to 8 hours). A mean apparent oral elimination clearance of 21.8 ml/min/kg compared favorably with that seen in other pregnant and nonpregnant populations. Food delayed the time to peak serum concentration to approximately 60 minutes. Labetalol was detected in fetal cord samples and amniotic fluid samples at concentrations approximately 50% and 16% that of simultaneous maternal vein samples, respectively. (AM J OBSTET GYNECOL 1990;162:362-6.)
Key words: Pharmacokinetics, labetalol, pregnancy-induced hypertension Labetalol is an antihypertensive agent that possesses selective postsynaptic a-adrenergic and nonselective !3-adrenergic receptor antagonism. In addition it may possess intrinsic agonist activity at !32-receptors, as it has been shown to block spontaneous and acetylcholine-induced uterine contractions in rats. Be-
From the Division of Maternal! Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee College of Medicine, and the Department of Pharmacy, Regional MedIcal Center. Presented at the Seventh Annual Meeting of the SocIety of Perlnatal Obstetricians, Lake Buena Vista, Florida, February 5-7, 1987. Received for publicatIOn May 1, 1989; reVISed July 19, 1989; accepted September 29, 1989. Reprint requests: Baha M. Sibaz, MD, DiVISion of Maternal! Fetal Medicine, Department of ObstetrICS and Gynecology, Unlverstty of Tennessee College of MediCine, 800 Madison Ave., MemphIS, TN 38163.
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cause of this unique combination of pharmacologic properties, labetalol produces direct vasodilation to decrease total peripheral resistance without changing resting heart rate and cardiac output. Labetalol has been used in the treatment of pregnancy-induced hypertension. Rapid reductions in blood pressure occur after oral and intravenous dosing. 1. 2 Studies of utero placental blood flow indicate that a decrease in placental perfusion does not occur, despite a significant reduction in maternal blood pressure. 3 Pregnancy can influence the pharmacokinetic and pharmacodynamic disposition of many drugs, but pharmacokinetic data in pregnant patients are often limited. Rubin et al.' studied half-life and clearance of a single intravenous dose oflabetalol in 10 antepartum women, 7 of the same women post partum, and in 10 normotensive nonpregnant female volunteers. Other studies have evaluated chronic labetalol oral dosing in
Labetalol in pregnancy
Volume 162 Number 2
363
Table I. Demographic and pharmacokinetic data, group means, and SD after oral administration of labetalol 100 mg after achievement of steady state Welght (kg)
PatIent
1 2 3 4 5 6 7 8
Mean (SD)
34 34 24 32 25 29 32 28 29.7 (3.8)
88 79.5 49 90.5 97.7 76.4 78.2 66 78.2 (15.3)
24 27 15 16 20 16 15 17 19 (4.5)
920 870 880 840 1020
NA
460 1180 881 (219)
43 35 25 42 40 35 35 33 36 (6)
1.9 1.5 1.3 1.8 1.9 2.0 1.6 1.3 1.7 (0.27)
.AUC (ng· hrlml)
Clo (mll mzn I kg)
1077 1715 1345 995 929 662 731 1211 1083 (342)
17.6 12.2 25.3 18.5 18.4 33.0 29.2 20.8 21.8 (6.8)
NA, Not available; C_" maximum serum concentration; Cm" , serum concentration nadir; 1m , elimination half-life; AUC, area under the concentration versus time curve; C/o. apparent oral elimination clearance.
pregnancy, I. 5. 6 but only one study included serum collection for concentration determination.' However, that study' did not attempt pharmacokinetic analysis because of a limited number of samples. Therefore the purpose of this study was to evaluate labetalol's pharmacokinetic parameters after chronic oral dosing. This information, in conjunction with hemodynamic evaluations, could aid in the establishment of appropriate dosing guidelines for labetalol in pregnant patients if the pharmacokinetic disposition was found to differ from that found in the nonpregnant population. A second purpose was to measure placental transfer of labetalol so that this information would be available when perinatal safety of labetalol is assessed. Material and methods This study was approved by the Institutional Review Board in conjunction with a 200-patient evaluation of labetalol plus hospitalization versus hospitalization alone. 7 Eight patients randomized to receive labetalol in the referenced study gave informed consent to participate in the present pharmacokinetic analysis. Patients were in the last trimester of pregnancy and had persistent elevations of blood pressure (systolic > 140 to 160 mm Hg or diastolic >90 to 110 mm Hg) 24 hours after hospitalization. Other laboratory evidence of mild preeclampsia included proteinuria (>300 mg/24 hours) and uricemia (>4.6 mg/dl). Patients had no medical or obstetric complications. Prescribed medications included prenatal vitamins and iron supplements. There were no dietary restrictions, but patients were confined to bed rest. Labetalol 100 mg every 8 hours was administered orally at 6 AM, 2 PM, and 10 PM. The study interval took place after at least 48 hours of chronic dosing to achieve steady state. The time of 48 hours was chosen on the basis of an average serum elimination half-life of 6 to 8 hours in nonpregnant patients, and the fact that it takes five half-lives to reach a pharmacokinetic steady state. A 5 ml blood sample obtained 8 hours after the
last dose was defined as time 0 for the study interval. The patient then ingested the study dose of labetalol 100 mg. Postdose blood samples were obtained at 20, 40,60,90, 120,240,360, and 480 minutes. The samples were centrifuged within 30 minutes of collection, and the serum was stored at - 20° C until analysis. Simultaneous maternal and fetal cord blood samples were collected at the time of delivery for labetalol concentration. In addition, simultaneous maternal and fetal cord blood samples obtained for other laboratory assessment from eight patients receiving labetalol in the 200-patient study were saved for labetalol concentration determination. Therefore the total number of paired samples was 16. Amniotic fluid samples were collected from six patients who underwent cesarean section and received labetalol in the 200-patient study. These samples were also stored at - 20° C. Samples were analyzed by high-performance liquid chromatography with the method outlined by Wood et al. 8 A highperformance liquid chromatograph (Hewlett Packard 1084, Avondale, Penn.) equipped with variable wavelength ultraviolet detector was used for analysis. Separation was achieved with a LiChrosorb RP-18 column (10 J,Lm, 20 cm x 4.6 mm) for both serum and amniotic fluid. Percentage recovery was >86%. Serum samples spiked with labetalol 125 ng/ml revealed a coefficient of variation of 4.3%. The assay's lower limit of sensitivity was < 10 ng/ml. Samples were run in duplicate. The elimination rate constant (ke) was calculated from least-squares regression analysis of the terminal exponential log plasma concentration versus time profile, assuming a one-compartment model (Macintosh Statworks, Cupertino, Calif.). The terminal elimination half-life (t~2) was calculated from equation I: t~2 =
0.693/ke
Noncompartmental analysis was used to estimate clearance and area under the serum concentration versus time curve because this method does not assume
364
Rogers, Sibai, and Whybrew
February 1990 Am J Obstet Gynecol
8
c
~
l!!
'E Q)
Patient2 .... Patient 1
-0-
6
u
c 0
..
4
c
2
(.)
E ::;, Q)
rn
...J
0 0
100
200
300
400
500
Time in Minutes Fig. 1. :\.tllll.tllogarithm (Ln) serum drug concentratlon versus lime aher oral administration of labetalol 100 mg in patients I and 2.
that the elimination data fit a chosen model. 9 The area under the serum concentration versus time curve was calculated with the trapezoidal rule. Apparent elimination clearance, an estimate of intrinsic liver clearance for high clearance drugs like labetalol, was expressed in relation to actual body weight and was calculated from equation 2: CI
= dose per kg body weight
o
AUC 0-8
where Clo = apparent oral clearance and AUC 08 = area under the concentration versus time curve from 0 to 8 hours. The fetall maternal serum ratio at time of delivery was calculated as fetal cord serum concentration/maternal serum concentration. The amniotic fluid/maternal serum ratio was calculated in a like manner. Results
The eight patients were similar in weeks' gestation (mean, 29.7 ± 3.8 weeks), age (mean, 19 ± 4.5 years), and weight (mean, 78.2 ± 15.3 kg), as described in Table I. There were seven primigravidous patients and one gravida 2, para 0 patient. Initial blood pressure averaged 142/91 mm Hg, with an average during therapy of 131182 mm Hg. Labetalol was well tolerated by all patients with no adverse effects reported. The natural logarithm serum drug concentration versus time plot for patients 1 and 2 is shown in Fig. 1. The mean time 0 serum concentration was 39.3 ± 41 ng/ml, and the mean 480-minute serum concentration was 36 ± 6 ng/ml, indicating that the study interval was indeed performed after achievement of steady state. Labetalol exhibited very rapid absorption with the peak serum concentration occurring at 20 minutes, which was the
timing of the first sam pie collection, in six patients. Peak serum concentration was delayed and occurred at 60 minutes in patients 2 and 3. On chart review it was found that samples were collected between 6 AM and 2 PM in these two patients, and that they ate breakfast during the first hour after the labetalol study dose. Labetalol disposition was biphasic. All patients entered the terminal elimination phase at approximately 90 minutes after drug ingestion. The demographic and pharmacokinetic parameters are described in Table I. Food ingestion increased the area under the serum concentration versus time curve but did not affect apparent elimination clearance, terminal elimination half-life, or the peak serum concentration obtained. The fetal cord/maternal serum ratio and amniotic fluid/maternal serum ratio at time of delivery are described in Fig. 2. These were found to be 0.5 ± 0.15 and 0.16 ± 0.13, respectively. Comment
The pathophysiologic changes that take place during pregnancy can affect drug disposition and may ultimately be responsible for an altered pharmacologic activity. Our patients achieved a mean peak labetalol serum concentration of 881 ± 219 ng/ ml 20 minutes after a 100 mg dose. A previous study of peak concentrations with oral dosing described peak serum concentration in the range of 96 to 250 mg/ml in nonpregnant hypertensive subjects. \0 The difference is thought not to be a result of a difference in patient populations, but to a difference in assay technique. The previous study was performed spectrofluorimetrically, whereas we used a more sensitive high-performance liquid chromatography method. Other reasons for dis-
Labetalol in pregnancy 365
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100
0 80 Fetal Cord: Maternal Vein Ratio: O.5±O.15
0 0
60
Amniotic Auid: Maternal Vein Ratio: O.16±O.13
ngIml 40
20
§
•• I •• Fetal
0 0
8
•
Maternal
Amniotic
Fig. 2. Fetal cord, ma ter nal vein , and amHlOl1C HUld (.oncentl'd110ll> at Iduetalol at time of delivery.
crepancies in reported peak serum concentration may be attributed to sampling time and product bioavailability. Two of our patients ate breakfast immediately after ingestion of the study dose. Their apparent elimination clearance was not significantly different from the other patients, which helps to confirm that patients were at steady state. Food ingestion resulted in a delay in time to peak serum concentration and an increased area under the serum concentration vesus time curve. This has been reported in a controlled study of the influence of food on labetalol absorption." One theory is that an increase in splanchnic blood flow caused by food may decrease the extraction ratio of high-clearance drugs, resulting in increased systemic bioavailability because there is less contact with metabolizing enzymes. '2 Whether the increased bioavaila bility improves pharmacologic effect has not been addressed. Rubin et a!." evaluated labetalol half-life and clearance after intravenous administration in 10 women with pregnancy-induced hypertension in the last trimester of pregnancy. They found a mean terminal elimination half-life of 2.4 hours and a mean drug clearance of 24.8 mIlmin / kg. This compares favorably with our findings of a mean 1.7 hour half-life and a mean apparent elimination clearance of 21.8 ::':: 6.8 mllmin/kg. Labetalol half-life in normotensive male volunteers and in nonpregnant hypertensive subjects has been found to vary considerably from 3 to 8 hours. '0. " This wide variation may be a result of the wide biologic variation in half-life, but may also be a result of a variation in compartmentalization modeling between studies. Total body clearance has been found to range from 19 to 33 mIlmin/kg in nonpregnant persons with normal renal and hepatic function," values that are also comparable to those in the present
study, which indicates clearance is not altered by pregnancy. The fetal cord/maternal serum ratio of approximately 0.5 found by Michael' a nd Nylund et al:' was confirmed in our study. The three studies have evaluated this ratio in patients who received varying doses at varying times before delivery. Whereas the concentrations differed, the mean ratio remained constant. A low amniotic fluid / maternal serum ratio has also been reported by Lunnell. ,:; Whereas bradyca rdia, hypotension, hypoglycemia , and a blunted response to stress are potential side effects after exposure to J3-adrenergic antagonists, the occurrence of these in infants exposed to labetalol in utero has been sporadic despite platen tal transfer of the drug. In this study of labetalol in pregnant patients with mild pregnancy-induced hypertension we found a shorter labetalol serum half-life but similar labetalol clearance , as compared with those of nonpregnant hypertensive and normotensive populations. This adds to our knowledge of the pharmacokinetic disposition of orally administered labetalol in pregnancy. REFERENCES I. Lamming CD, Symonds EM. Use of labetalol and methyldopa in pregnancy-induced hypertension. Br J Clin Pharmacol 1979;8:217S. 2. Walker JJ. Calder AA, Greer J. Treatment of acute pregnancy-related hypertension : labetalol and hydralazine compared. Postgrad Med J 1983;59(suppl 3): 168. 3. Nylund L, Lunnell NO, Lewander R, et a1. Labetalol for the treatment of hypertension in pregnancy. Acta Obstet Gynecol Scand 1984; 118:71. 4. Rubin PC. Butters L, Kelman AW, et a1. Labetalol disposition and concentration-effect relationships during pregnancy. Br J Clm Pharmacol 1983;15:465. 5. Michael CA. Use of labetalol in the treatment of severe hypertension during pregnancy. Br J Clin Pharmacol 1979;8:21IS. 6. Michael CA. The evaluation of labetalol in the treatment
Rogers, Sibai, and Whybrew
7.
8. 9. 10.
11.
of hypertension complicating pregnancy. Br J Clin PharmacoI1982;13:128S. Sibai BM, Gonzalez AR, Mabie WC, Moretti M. A comparison of labetalol plus hospitalization versus hospitalization alone in the management of preeclampsia remote from term. Obstet Gynecol 1987;70:323. Wood AJ, Ferry DG, Bailey RR. Elimination kinetics of labetalol in severe renal failure. Br J Clin Pharmacol 1982;13:81S. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982. McNeil JJ, Anderson AE, Louis WJ, Morgan DJ. Pharmacokinetics and pharmacodynamic studies of labetalol in hypertensive subjects. Br J Clin Pharmacol 1979; 8: 157S. Daneshmend TK, Roberts CJC. The influence offood on
February 1990
Am J Obstet Gynecol
12. 13. 14. 15.
the oral and Intravenous pharmacokinetics of a high clearance drug: a study with labetalol. Br J Clin Pharmacol 1982; 14:73. McClean AJ, McNamara PJ, duSouch P, et al. Foods, splanchnic blood flow and bioavailability of drugs subject to first pass metabolism. Clin Pharmacol Ther 1978;24:5. Chung M, Leitz FH, Maier G, et al. Rising multiple-dose pharmacokinetics of labetalol in hypertensive patients. J Clin Pharmacol 1986;26:248. McEvoy GK, McQuarrie GM, eds. American hospital formulary service drug information. Bethesda, Maryland: American Society of Hospital Pharmacists, 1986. Lunnell NO, Kulas J, Rane A. Transfer of labetalol into amniotic fluid and breast milk in lactating women. Eur J Clin Pharmacol 1985;28:597.
Proteinuria and outcome of 444 pregnancies complicated by hypertension Sergio Ferrazzani, MD, Alessandro Caruso, MD, Sara De Carolis, MD, Ida Vercillo Martino, MD, and Salvatore Mancuso, MD Rome, Italy The purpose of this study was to determine the role of proteinuria on pregnancy outcome in 444 hypertensive women with Singleton pregnancies. The patients were divided into three hypertensive groups: 98 with chronic hypertension, 199 with nonproteinuric gestational hypertension, and 147 with proteinuric preeclampsia and chronic hypertension with superimposed proteinuric preeclampsia. The presence of increased proteinuria (>0.3 gm/L) predicted an adverse pregnancy outcome. Furthermore, the majority of small-for-gestational-age infants occurred in the group with proteinuric preeclampsia (52%), whereas the rate of small-for-gestational-age infants was 18% and 12% in the group with nonproteinuric gestational hypertension and chronic hypertension, respectively. The group with chronic hypertension did not show any increased risk for fetal outcome. Perinatal mortality rate was extremely poor in the group with proteinuric preeclampsia at 129 per 1000, four times higher than those of the other two groups. (AM J OBSTET GVNECOL 1990;162:366-71.)
Key words: Proteinuria, hypertension, pregnancy outcome
Hypertension in pregnancy is the major cause of fetal growth retardation and perinatal mortality. The influence of hypertension on fetal growth may differ according to the type of disease that affects the pregnant woman. I.7 Whether the different diseases that cause hypertension during pregnancy have similarly
From the Department of Obstetrics and Gynecology, Catholzc University. Receivedfor publication May 5,1989; revised September 11, 1989; accepted September 20, 1989. Reprint requests: Sergto Ferrazzani, Clinica Ostetrica e Ginecologica, Univemtit Cattolica del S. Cuore, Largo AgostinO Gemelli 8, 00168 Rome, Italy. 611/16824
366
adverse effects on fetal outcome is a matter of controversy.I.7 The cause of these discrepancies seems to be related to the different diagnostic criteria used. In patients with chronic hypertension, the appearance of proteinuria is associated with increased perinatal loss. 1. 2. 5. 6 For some authors gestational hypertension without proteinuria does not seem to affect fetal growth. 1.3 protein uric gestational hypertension is unequivocally considered a disease with severe fetal consequences. [.4.8 This article describes the role of proteinuria in 444 hypertensive pregnant women to evaluate the relationship between proteinuria, type of hypertension, and birth weight.
6.
7.
8.
9. 10.
bryonic and adult human tissues.] Cell Sci 1987;88:41930. Peters ]H, Maunder R, Woolf A, Cochrane CG, Ginsberg MH. Elevated plasma levels of ED 1 + ("cellular") fibronectin in patients with vascular injury. ] Lab Clin Med 1989; 113 :586-97. Lazarchick], Stubbs TM, Romein L. Predictive value of fibronectin levels in normotensive gravid women destined to become preeclamptic. AM] OBSTET GYNECOL 1986; 154: 1050-2. Stubbs TM, Lazarchick], Horger EO. Plasma fibronectin levels in preeclampsia: a possible biochemical marker for vascular endothelial damage. AM ] OBSTET GYNECOL 1984;150:885-7. Saleh AA, Bottoms SF, Welch RA, et al. Preeclampsia, delivery, and the hemostatic system. AM ] OBSTET GyNECOL 1987;157:331-5. Peters ]H, Ginsberg MH, Case CM, Cochrane CH. Release of soluble fibronectin containing an extra type III domain (ED1) during acute pulmonary injury mediated by oxidants or leukocytes in vivo. Am Rev Respir Dis 1988; 138: 167-74.
February 1990 Am J Obstet Gynecol
11. Peters ]H, Ginsberg MH, Bohl BP, Sklar LA, Cochrane CG. Intravascular release of intact cellular fibronectin during oxidant-induced injury of the in vitro perfused rabbit lung.] Clin Invest 1986;78:1596-603. 12. Rodgers GM, Taylor RN, Roberts ]M. Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells. AM] OBSTET GYNECOL 1988;159:908-14. 13. Annunciado AN, Stubbs TM, Pepkowitz SH, et al. Altered villus vessel fibronectin in preeclampsia. AM ] 08STET GYNECOL 1987; 156:898-900. 14. Paul]I, Schwarzbauer ]E, Tamkun]W, Hynes RO. Celltype specific fibronectin subunits generated by alternative splicing. ] Bioi Chern 1986;261: 12258-65. 15. Pick-Kober KH, Munker D, Gressner AM. Fibronectin is synthesized as an acute phase reactant in rat hepatocytes. ] Clin Chern Clin Biochem 1986;24:521-8. 16. Cosio FG, Bakaletz AP. Abnormal plasma fibronectin levels in patients with proteinuria. ] Lab Clin Med 1984; 104:863.
Labetalol pharmacokinetics in pregnancy-induced hypertension Rebecca C. Rogers, PharrnD, Baha M. Sibai, MD, and W. David Whybrew, MS Memphis, Tennessee Pharmacokinetic parameters of oral labetalol were studied in eight women with pregnancy-induced hypertension in the third trimester of pregnancy. Labetalol exhibited rapid absorption; peak serum concentrations of 881 ± 219 ng/ml occurred at 20 minutes after labetalol ingestion. The terminal elimination half-life (mean, 1.7 ± 0.27 hours) was found to be shorter than that reported for normotensive volunteers or nonpregnant hypertensive patients (mean, 6 to 8 hours). A mean apparent oral elimination clearance of 21.8 ml/min/kg compared favorably with that seen in other pregnant and nonpregnant populations. Food delayed the time to peak serum concentration to approximately 60 minutes. Labetalol was detected in fetal cord samples and amniotic fluid samples at concentrations approximately 50% and 16% that of simultaneous maternal vein samples, respectively. (AM J OBSTET GYNECOL 1990;162:362-6.)
Key words: Pharmacokinetics, labetalol, pregnancy-induced hypertension Labetalol is an antihypertensive agent that possesses selective postsynaptic a-adrenergic and nonselective !3-adrenergic receptor antagonism. In addition it may possess intrinsic agonist activity at !32-receptors, as it has been shown to block spontaneous and acetylcholine-induced uterine contractions in rats. Be-
From the Division of Maternal! Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee College of Medicine, and the Department of Pharmacy, Regional MedIcal Center. Presented at the Seventh Annual Meeting of the SocIety of Perlnatal Obstetricians, Lake Buena Vista, Florida, February 5-7, 1987. Received for publicatIOn May 1, 1989; reVISed July 19, 1989; accepted September 29, 1989. Reprint requests: Baha M. Sibaz, MD, DiVISion of Maternal! Fetal Medicine, Department of ObstetrICS and Gynecology, Unlverstty of Tennessee College of MediCine, 800 Madison Ave., MemphIS, TN 38163.
6/1117012
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cause of this unique combination of pharmacologic properties, labetalol produces direct vasodilation to decrease total peripheral resistance without changing resting heart rate and cardiac output. Labetalol has been used in the treatment of pregnancy-induced hypertension. Rapid reductions in blood pressure occur after oral and intravenous dosing. 1. 2 Studies of utero placental blood flow indicate that a decrease in placental perfusion does not occur, despite a significant reduction in maternal blood pressure. 3 Pregnancy can influence the pharmacokinetic and pharmacodynamic disposition of many drugs, but pharmacokinetic data in pregnant patients are often limited. Rubin et al.' studied half-life and clearance of a single intravenous dose oflabetalol in 10 antepartum women, 7 of the same women post partum, and in 10 normotensive nonpregnant female volunteers. Other studies have evaluated chronic labetalol oral dosing in
Labetalol in pregnancy
Volume 162 Number 2
363
Table I. Demographic and pharmacokinetic data, group means, and SD after oral administration of labetalol 100 mg after achievement of steady state Welght (kg)
PatIent
1 2 3 4 5 6 7 8
Mean (SD)
34 34 24 32 25 29 32 28 29.7 (3.8)
88 79.5 49 90.5 97.7 76.4 78.2 66 78.2 (15.3)
24 27 15 16 20 16 15 17 19 (4.5)
920 870 880 840 1020
NA
460 1180 881 (219)
43 35 25 42 40 35 35 33 36 (6)
1.9 1.5 1.3 1.8 1.9 2.0 1.6 1.3 1.7 (0.27)
.AUC (ng· hrlml)
Clo (mll mzn I kg)
1077 1715 1345 995 929 662 731 1211 1083 (342)
17.6 12.2 25.3 18.5 18.4 33.0 29.2 20.8 21.8 (6.8)
NA, Not available; C_" maximum serum concentration; Cm" , serum concentration nadir; 1m , elimination half-life; AUC, area under the concentration versus time curve; C/o. apparent oral elimination clearance.
pregnancy, I. 5. 6 but only one study included serum collection for concentration determination.' However, that study' did not attempt pharmacokinetic analysis because of a limited number of samples. Therefore the purpose of this study was to evaluate labetalol's pharmacokinetic parameters after chronic oral dosing. This information, in conjunction with hemodynamic evaluations, could aid in the establishment of appropriate dosing guidelines for labetalol in pregnant patients if the pharmacokinetic disposition was found to differ from that found in the nonpregnant population. A second purpose was to measure placental transfer of labetalol so that this information would be available when perinatal safety of labetalol is assessed. Material and methods This study was approved by the Institutional Review Board in conjunction with a 200-patient evaluation of labetalol plus hospitalization versus hospitalization alone. 7 Eight patients randomized to receive labetalol in the referenced study gave informed consent to participate in the present pharmacokinetic analysis. Patients were in the last trimester of pregnancy and had persistent elevations of blood pressure (systolic > 140 to 160 mm Hg or diastolic >90 to 110 mm Hg) 24 hours after hospitalization. Other laboratory evidence of mild preeclampsia included proteinuria (>300 mg/24 hours) and uricemia (>4.6 mg/dl). Patients had no medical or obstetric complications. Prescribed medications included prenatal vitamins and iron supplements. There were no dietary restrictions, but patients were confined to bed rest. Labetalol 100 mg every 8 hours was administered orally at 6 AM, 2 PM, and 10 PM. The study interval took place after at least 48 hours of chronic dosing to achieve steady state. The time of 48 hours was chosen on the basis of an average serum elimination half-life of 6 to 8 hours in nonpregnant patients, and the fact that it takes five half-lives to reach a pharmacokinetic steady state. A 5 ml blood sample obtained 8 hours after the
last dose was defined as time 0 for the study interval. The patient then ingested the study dose of labetalol 100 mg. Postdose blood samples were obtained at 20, 40,60,90, 120,240,360, and 480 minutes. The samples were centrifuged within 30 minutes of collection, and the serum was stored at - 20° C until analysis. Simultaneous maternal and fetal cord blood samples were collected at the time of delivery for labetalol concentration. In addition, simultaneous maternal and fetal cord blood samples obtained for other laboratory assessment from eight patients receiving labetalol in the 200-patient study were saved for labetalol concentration determination. Therefore the total number of paired samples was 16. Amniotic fluid samples were collected from six patients who underwent cesarean section and received labetalol in the 200-patient study. These samples were also stored at - 20° C. Samples were analyzed by high-performance liquid chromatography with the method outlined by Wood et al. 8 A highperformance liquid chromatograph (Hewlett Packard 1084, Avondale, Penn.) equipped with variable wavelength ultraviolet detector was used for analysis. Separation was achieved with a LiChrosorb RP-18 column (10 J,Lm, 20 cm x 4.6 mm) for both serum and amniotic fluid. Percentage recovery was >86%. Serum samples spiked with labetalol 125 ng/ml revealed a coefficient of variation of 4.3%. The assay's lower limit of sensitivity was < 10 ng/ml. Samples were run in duplicate. The elimination rate constant (ke) was calculated from least-squares regression analysis of the terminal exponential log plasma concentration versus time profile, assuming a one-compartment model (Macintosh Statworks, Cupertino, Calif.). The terminal elimination half-life (t~2) was calculated from equation I: t~2 =
0.693/ke
Noncompartmental analysis was used to estimate clearance and area under the serum concentration versus time curve because this method does not assume
364
Rogers, Sibai, and Whybrew
February 1990 Am J Obstet Gynecol
8
c
~
l!!
'E Q)
Patient2 .... Patient 1
-0-
6
u
c 0
..
4
c
2
(.)
E ::;, Q)
rn
...J
0 0
100
200
300
400
500
Time in Minutes Fig. 1. :\.tllll.tllogarithm (Ln) serum drug concentratlon versus lime aher oral administration of labetalol 100 mg in patients I and 2.
that the elimination data fit a chosen model. 9 The area under the serum concentration versus time curve was calculated with the trapezoidal rule. Apparent elimination clearance, an estimate of intrinsic liver clearance for high clearance drugs like labetalol, was expressed in relation to actual body weight and was calculated from equation 2: CI
= dose per kg body weight
o
AUC 0-8
where Clo = apparent oral clearance and AUC 08 = area under the concentration versus time curve from 0 to 8 hours. The fetall maternal serum ratio at time of delivery was calculated as fetal cord serum concentration/maternal serum concentration. The amniotic fluid/maternal serum ratio was calculated in a like manner. Results
The eight patients were similar in weeks' gestation (mean, 29.7 ± 3.8 weeks), age (mean, 19 ± 4.5 years), and weight (mean, 78.2 ± 15.3 kg), as described in Table I. There were seven primigravidous patients and one gravida 2, para 0 patient. Initial blood pressure averaged 142/91 mm Hg, with an average during therapy of 131182 mm Hg. Labetalol was well tolerated by all patients with no adverse effects reported. The natural logarithm serum drug concentration versus time plot for patients 1 and 2 is shown in Fig. 1. The mean time 0 serum concentration was 39.3 ± 41 ng/ml, and the mean 480-minute serum concentration was 36 ± 6 ng/ml, indicating that the study interval was indeed performed after achievement of steady state. Labetalol exhibited very rapid absorption with the peak serum concentration occurring at 20 minutes, which was the
timing of the first sam pie collection, in six patients. Peak serum concentration was delayed and occurred at 60 minutes in patients 2 and 3. On chart review it was found that samples were collected between 6 AM and 2 PM in these two patients, and that they ate breakfast during the first hour after the labetalol study dose. Labetalol disposition was biphasic. All patients entered the terminal elimination phase at approximately 90 minutes after drug ingestion. The demographic and pharmacokinetic parameters are described in Table I. Food ingestion increased the area under the serum concentration versus time curve but did not affect apparent elimination clearance, terminal elimination half-life, or the peak serum concentration obtained. The fetal cord/maternal serum ratio and amniotic fluid/maternal serum ratio at time of delivery are described in Fig. 2. These were found to be 0.5 ± 0.15 and 0.16 ± 0.13, respectively. Comment
The pathophysiologic changes that take place during pregnancy can affect drug disposition and may ultimately be responsible for an altered pharmacologic activity. Our patients achieved a mean peak labetalol serum concentration of 881 ± 219 ng/ ml 20 minutes after a 100 mg dose. A previous study of peak concentrations with oral dosing described peak serum concentration in the range of 96 to 250 mg/ml in nonpregnant hypertensive subjects. \0 The difference is thought not to be a result of a difference in patient populations, but to a difference in assay technique. The previous study was performed spectrofluorimetrically, whereas we used a more sensitive high-performance liquid chromatography method. Other reasons for dis-
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Fig. 2. Fetal cord, ma ter nal vein , and amHlOl1C HUld (.oncentl'd110ll> at Iduetalol at time of delivery.
crepancies in reported peak serum concentration may be attributed to sampling time and product bioavailability. Two of our patients ate breakfast immediately after ingestion of the study dose. Their apparent elimination clearance was not significantly different from the other patients, which helps to confirm that patients were at steady state. Food ingestion resulted in a delay in time to peak serum concentration and an increased area under the serum concentration vesus time curve. This has been reported in a controlled study of the influence of food on labetalol absorption." One theory is that an increase in splanchnic blood flow caused by food may decrease the extraction ratio of high-clearance drugs, resulting in increased systemic bioavailability because there is less contact with metabolizing enzymes. '2 Whether the increased bioavaila bility improves pharmacologic effect has not been addressed. Rubin et a!." evaluated labetalol half-life and clearance after intravenous administration in 10 women with pregnancy-induced hypertension in the last trimester of pregnancy. They found a mean terminal elimination half-life of 2.4 hours and a mean drug clearance of 24.8 mIlmin / kg. This compares favorably with our findings of a mean 1.7 hour half-life and a mean apparent elimination clearance of 21.8 ::':: 6.8 mllmin/kg. Labetalol half-life in normotensive male volunteers and in nonpregnant hypertensive subjects has been found to vary considerably from 3 to 8 hours. '0. " This wide variation may be a result of the wide biologic variation in half-life, but may also be a result of a variation in compartmentalization modeling between studies. Total body clearance has been found to range from 19 to 33 mIlmin/kg in nonpregnant persons with normal renal and hepatic function," values that are also comparable to those in the present
study, which indicates clearance is not altered by pregnancy. The fetal cord/maternal serum ratio of approximately 0.5 found by Michael' a nd Nylund et al:' was confirmed in our study. The three studies have evaluated this ratio in patients who received varying doses at varying times before delivery. Whereas the concentrations differed, the mean ratio remained constant. A low amniotic fluid / maternal serum ratio has also been reported by Lunnell. ,:; Whereas bradyca rdia, hypotension, hypoglycemia , and a blunted response to stress are potential side effects after exposure to J3-adrenergic antagonists, the occurrence of these in infants exposed to labetalol in utero has been sporadic despite platen tal transfer of the drug. In this study of labetalol in pregnant patients with mild pregnancy-induced hypertension we found a shorter labetalol serum half-life but similar labetalol clearance , as compared with those of nonpregnant hypertensive and normotensive populations. This adds to our knowledge of the pharmacokinetic disposition of orally administered labetalol in pregnancy. REFERENCES I. Lamming CD, Symonds EM. Use of labetalol and methyldopa in pregnancy-induced hypertension. Br J Clin Pharmacol 1979;8:217S. 2. Walker JJ. Calder AA, Greer J. Treatment of acute pregnancy-related hypertension : labetalol and hydralazine compared. Postgrad Med J 1983;59(suppl 3): 168. 3. Nylund L, Lunnell NO, Lewander R, et a1. Labetalol for the treatment of hypertension in pregnancy. Acta Obstet Gynecol Scand 1984; 118:71. 4. Rubin PC. Butters L, Kelman AW, et a1. Labetalol disposition and concentration-effect relationships during pregnancy. Br J Clm Pharmacol 1983;15:465. 5. Michael CA. Use of labetalol in the treatment of severe hypertension during pregnancy. Br J Clin Pharmacol 1979;8:21IS. 6. Michael CA. The evaluation of labetalol in the treatment
Rogers, Sibai, and Whybrew
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8. 9. 10.
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of hypertension complicating pregnancy. Br J Clin PharmacoI1982;13:128S. Sibai BM, Gonzalez AR, Mabie WC, Moretti M. A comparison of labetalol plus hospitalization versus hospitalization alone in the management of preeclampsia remote from term. Obstet Gynecol 1987;70:323. Wood AJ, Ferry DG, Bailey RR. Elimination kinetics of labetalol in severe renal failure. Br J Clin Pharmacol 1982;13:81S. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982. McNeil JJ, Anderson AE, Louis WJ, Morgan DJ. Pharmacokinetics and pharmacodynamic studies of labetalol in hypertensive subjects. Br J Clin Pharmacol 1979; 8: 157S. Daneshmend TK, Roberts CJC. The influence offood on
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the oral and Intravenous pharmacokinetics of a high clearance drug: a study with labetalol. Br J Clin Pharmacol 1982; 14:73. McClean AJ, McNamara PJ, duSouch P, et al. Foods, splanchnic blood flow and bioavailability of drugs subject to first pass metabolism. Clin Pharmacol Ther 1978;24:5. Chung M, Leitz FH, Maier G, et al. Rising multiple-dose pharmacokinetics of labetalol in hypertensive patients. J Clin Pharmacol 1986;26:248. McEvoy GK, McQuarrie GM, eds. American hospital formulary service drug information. Bethesda, Maryland: American Society of Hospital Pharmacists, 1986. Lunnell NO, Kulas J, Rane A. Transfer of labetalol into amniotic fluid and breast milk in lactating women. Eur J Clin Pharmacol 1985;28:597.
Proteinuria and outcome of 444 pregnancies complicated by hypertension Sergio Ferrazzani, MD, Alessandro Caruso, MD, Sara De Carolis, MD, Ida Vercillo Martino, MD, and Salvatore Mancuso, MD Rome, Italy The purpose of this study was to determine the role of proteinuria on pregnancy outcome in 444 hypertensive women with Singleton pregnancies. The patients were divided into three hypertensive groups: 98 with chronic hypertension, 199 with nonproteinuric gestational hypertension, and 147 with proteinuric preeclampsia and chronic hypertension with superimposed proteinuric preeclampsia. The presence of increased proteinuria (>0.3 gm/L) predicted an adverse pregnancy outcome. Furthermore, the majority of small-for-gestational-age infants occurred in the group with proteinuric preeclampsia (52%), whereas the rate of small-for-gestational-age infants was 18% and 12% in the group with nonproteinuric gestational hypertension and chronic hypertension, respectively. The group with chronic hypertension did not show any increased risk for fetal outcome. Perinatal mortality rate was extremely poor in the group with proteinuric preeclampsia at 129 per 1000, four times higher than those of the other two groups. (AM J OBSTET GVNECOL 1990;162:366-71.)
Key words: Proteinuria, hypertension, pregnancy outcome
Hypertension in pregnancy is the major cause of fetal growth retardation and perinatal mortality. The influence of hypertension on fetal growth may differ according to the type of disease that affects the pregnant woman. I.7 Whether the different diseases that cause hypertension during pregnancy have similarly
From the Department of Obstetrics and Gynecology, Catholzc University. Receivedfor publication May 5,1989; revised September 11, 1989; accepted September 20, 1989. Reprint requests: Sergto Ferrazzani, Clinica Ostetrica e Ginecologica, Univemtit Cattolica del S. Cuore, Largo AgostinO Gemelli 8, 00168 Rome, Italy. 611/16824
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adverse effects on fetal outcome is a matter of controversy.I.7 The cause of these discrepancies seems to be related to the different diagnostic criteria used. In patients with chronic hypertension, the appearance of proteinuria is associated with increased perinatal loss. 1. 2. 5. 6 For some authors gestational hypertension without proteinuria does not seem to affect fetal growth. 1.3 protein uric gestational hypertension is unequivocally considered a disease with severe fetal consequences. [.4.8 This article describes the role of proteinuria in 444 hypertensive pregnant women to evaluate the relationship between proteinuria, type of hypertension, and birth weight.
