Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives

Transcription

1 Loraepam and oxaepam kinetics in women on low-dose oral contraceptives Women on low-dose estrogen oral contraceptives (OC) and drug-free control women matched for age, weight, and cigarette smoking habits, received single 2-mg IV doses of loraepam or single 30-mg oral doses of oxaepam, two benodiaepines metabolied by glucuronide conjugation. Kinetics were determined from multiple plasma concentrations measured during 48 hr after dosing. Mean kinetic variables for loraepam in control and OC groups (n = 15 in each group) were: volume of distribution (Vd), 1.33 and /kg: elimination t1/2, 13.1 and 12.2 hr; total clearance, 1.25 and 1.50 milminikg; free.fraction in plasma, 10.3% and 10.3% unbound. For oxaepam, kinetic variables in the two groups (n = 14 and 17) were: Vd, 1.05 and 1.19 Ilkg; t1/2, 7.6 and 7.2 hr; total clearance, 1.60 and 2.03 milminikg; free fraction, 4.6% and 4.9% unbound. None of these differences were significant. Thus, metabolic clearance by glucuronidation of loraepam and oxaepam is not significantly affected by OC, in contrast with the highly significant reduction in clearance of the oxidied benodiaepine diaepam. Darrell R. Abernethy, M.D., Ph.D., David J. Greenblatt, M.D., Hermann R. Ochs, M.D., Dagmar Weyers, Cand.Med., Marcia Divoll, B.S., Jerold S. Harmat, B.A., and Richard I. Shader, M.D. Boston, Mass., and Bonn, West Germany Division of Clinical Pharmacology, Departments of Psychiatry and Medicine, TuftsNew England Medical Center, Boston, and the Mediinische Universitiitsklinik, University of Bonn Oral contraceptives have the capacity to influence the kinetics of other drugs." Published reports indicate that oral contraceptives may impair metabolic clearance and prolong elimination t1/2 of drugs biotransformed by hepatic microsomal oxidative mechanisms, including antipyrine,2' 4' " diaepam,3 and caf- Supported in part by grant MH and AM-MH from the United States Public Health Service and by grant Oc 10/6-3 from Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, West Germany. Received for publication Sept. 4, Accepted for publication Dec. 11, Reprint requests to: Darrell R. Abernethy, M.D., Ph.D., Division of Clinical Pharmacology, Box 1007, New England Medical Center Hospital, 171 Harrison Ave., Boston, MA feine,13 but the effect of oral contraceptives on the disposition of drugs metabolied mainly by conjugation has not been extensively evaluated. We reported that the biotransformation of the analgesic-antipyretic agent acetaminophen was enhanced in oral contraceptive (OC) users, leading to increased metabolic clearance and shortened elimination t1/2.' The present study evaluated the effect of OCs on the disposition of oxaepam and loraepam, two benodiaepine derivatives biotransformed principally by conjugation to their respective glucuronates.6, 10 Methods Our subjects were healthy women from 19 to 37 yr old with similar smoking habits. One 628

2 Volume 33 Number 5 Oral contraceptives and loraepam and oxaepam kinetics _ it = OXAZEPAM, 30 mg PO / 0 Lu 20- o 6 io. ),,t, cr CONTROL O.C. CONTROL 0.C. a_ LORAZEPAM, 2 mg IV \\ Fig. 2. Elimination t1/2 (left) and total metabolic clearance (right) of loraepam in control subjects and OC recipients. Individual and mean (± SE) values are shown for each group. See Table I for statistical HOURS AFTER DOSE Fig. 1. Plasma concentrations of loraepam and oxaepam in an OC recipient who was given a single 2-mg IV dose of loraepam on one occasion and a 30-mg oral dose of oxaepam on another. group consisted of women taking low-dose estrogen OCs (50,u,g or less of ethinyl estradiol) for at least 3 mo before the study. Control subjects were taking no medications but were physically comparable to the OC recipients. Procedure for loraepam study. Control subjects and OC recipients (n = 15 in each roup) received a single 2-mg IV dose of loraepam by rapid injection. Venous blood samples were drawn into heparinied tubes before the dose, and several times over the next 48 hr. Plasma was separated and froen until assayed. Concentrations of loraepam in all plasma samples were determined by electron-capture gas-liquid chromatography.6' 9 For each subject the extent of loraepam protein binding was determined by equilibrium dialysis of a single sample drawn in the nonfasting state after addition of 33 ng/ml of 14C-loraepam (31 pci/ mg).5 Plasma loraepam concentrations were analyed by iterative nonlinear least-squares regression techniques.' Plasma concentrations were fitted to a linear sum of exponential terms (Fig. 1). Coefficients and exponents from the fitted functions were used to determine loraepam elimination t1/2, total volume of distribution (Vd) using the area method, and total metabolic clearance. Differences between control subjects and oral contraceptive recipients were subjected to Student's independent t test. Procedure for oxaepam study. Control subjects and OC recipients (n and 17) received a single 30-mg oral dose of oxaepam as two 15-mg tablets with 100 to 200 ml of tap water after an overnight fast. No other food or liquid was taken until 3 hr after the dose. Several venous blood samples were drawn during the 48 hr after the dose. Plasma was separated and froen until the time of assay. Oxaepam plasma concentrations were determined by electron-capture gas-liquid chromatography.6. 8' 9 The extent of oxaepam plasma protein binding was determined by equilibrium dialysis in a single sample drawn in the nonfasting state after addition of 46 ng/ml of 14Coxaepam (22,uCi/mg). Oxaepam elimination t1/2 was determined using the slope (0) of the terminal log-linear portion of the plasma concentration curve (Fig. 1). AUC until the final detectable plasma concentration was calculated

3 630 Abernethy et al. Clin. Pharmacol. Ther. May , E 12 Ui.c Li] Z.L e 8, a Li _J 4_ a_ S. Li NJ a x o 2_ g 2_ x CONTROL 0 C CONTROL 0 C ONTROL GC CONTROL 0 C Fig. 3. Free fraction in plasma of loraepam (left) and oxaepam (right) in control subjects and in OC recipients. Individual and mean (±SE) values are shown for each group. See Tables I and II for statistical Fig. 4. Elimination t1/2 (left) and total metabolic clearance (right) of oxaepam in control subjects and OC recipients. Individual and mean (± SE) values are shown for each group. See Table II for statistical Table I. Loraepam kinetics in control subjects and OC recipients (mean ± SE) Controls OC recipients Value of student's t Subject characteristics No. of subjects Age (yr) (NS) (± 1.7) (± 1.1) Weight (kg) (NS) (± 1.2) (± 1.3) Cigarette smoker (yes/no) 3/12 4/ (NS)* Kinetic variables for loraepam Vd (//kg) (NS) (±07) (±.06) Elimination t1/2 (hr) (NS) (± 0.8) (±1.2) Total clearance (ml/min/kg) (NS) (±0.1) (±0.1) Free fraction in plasma (% unbound) (NS) (:_f_-0.4) (±0.3) *This value obtained by chi-square by the trapeoidal method. To this was added the residual area extrapolated to infinity, calculated as the final concentration divided by p. Total clearance was calculated as dose/auc, assuming the entire 30-mg dose was available to the systemic circulation. Apparent Vd was calculated as clearance/o. Differences between control subjects and OC recipients were subjected to Student's independent t test. Results Loraepam study. Loraepam elimination t1/2 was much the same in control subjects and OC recipients (13.1 and 12.2 hr); total metabolic clearance (1.25 and 1.5 ml/min/kg; Table I, Fig. 2), Vd, and free fraction (Fig. 3) also did not differ significantly between groups. Oxaepam study. As in the case of loraepam, oxaepam elimination t1/2 in the OC group and in controls (7.2 and 7.6 hr) and total meta-

4 Volume 33 Number 5 Oral contraceptives and loraepam and oxaepam kinetics 631 Table II. Oxaepam kinetics in control subjects and in OC recipients Controls OC recipients Value of student's t Subject characteristics No. of subjects Age (yr) (NS) (± 0.6) (-± 1.1) Weight (kg) (P <0.05) (± 1.9) (±2.1) Cigarette smoking (yes/no) 6/8 4/ (NS)* Kinetic variables for oxaepam Vd (//kg) (NS) (±07) (±.14) Elimination t1/2 (hr) (NS) (±.6) (±.6) Total clearance (ml/min/kg) (NS) (± 0.1) (± 0.2) Free fraction in plasma (% unbound) (NS) (± 3) (-±.2) *This value obtained by chi-square bolic clearance in the two groups (2 and 1.6 ml/min/kg; Table II, Fig. 4) did not differ substantially. Vd and free fraction values also did not differ (Fig. 3). Discussion Studies of the kinetic profile of diaepam in a similar group of OC recipients and control subjects revealed impaired total metabolic clearance and prolonged elimination Ph in the OC group.3 The finding is consistent with impairment of hepatic microsomal oxidiing capacity, which is probably attributable to the estrogen content of the OC.12' 13 Similar results have been reported for other oxidatively metabolied drugs.2, 4, 11, 16 Preliminary findings, however, suggest that OCs do not have the same effect on kinetics of drugs metabolied by conjugation as on those that are oxidied. Enhanced metabolic clearance of acetaminophen has been observed in OC users.' Our study indicates that metabolic clearance of the conjugatively metabolied benodiaepines loraepam and oxaepam is not impaired by OCs. Clearance of both drugs was the same in the control and OC groups. Our findings and those from other studies indicate that OCs impair the clearance of certain oxidatively metabolied drugs, whereas they either enhance or leave unchanged the clearance of drugs metabolied by conjugation. In a preliminary report Patwardhan et al.16 suggest that there is enhanced oxaepam and loraepam clearance among women receiving OCs. The reason for the conflicting results is not clear, but may be related to sample sie since their study group was much smaller than ours. At present, the clinical implications of an interaction or noninteraction of OCs with benodiaepines is not established. It appears, however, that adjustment of dose of the conjugatively metabolied benodiaepines loraepam and oxaepam in women receiving OCs is not necessary. We are grateful for the assistance of Dr. Lawrence J. Moschitto, Ann Locniskar, Rita Maths, and the Staff of the Clinical Study Unit, New England Medical Center Hospital (Supported by USPHS grant RR-24040). References Abernethy DR, Divoll M, Ochs HR, Ameer B, Greenblatt DJ: Increased metabolic clearance of acetaminophen with oral contraceptive use. Obstet Gynecol 60: , Abernethy DR, Greenblatt DJ: Impairment of antipyrine metabolism by low-dose oral contraceptive steroids. CLIN PHARMACOL THER 29: , Abernethy DR, Greenblatt DJ, Divoll M, Arendt R, Ochs HR, Shader RI: Impairment of diaepam metabolism by low-dose estrogen oral con-

5 632 Abernethy et al. Clio. Pharmacol. Ther. May 1983 traceptive steroids. N Engl J Med 306: , Carter DE, Bressler R, Hughes MR, Haussler MR, Christian D, Heine MW: Effect of oral contraceptives on plasma clearance. CLIN PHAR- MACOL THER 18: , Divoll M, Greenblatt DJ: Effect of age and sex on loraepam protein binding. J Pharm Pharmacol 34: , Greenblatt DJ: Clinical pharmacokinetics of oxaepam and loraepam. Clin Pharmacokinet 6:89-105, Greenblatt DJ, Allen MD, Locniskar A, Harmat JS, Shader RI: Loraepam kinetics in the elderly. CLIN PHARMACOL THER 26: , Greenblatt DJ, Divoll M, Harmat JS, Shader RI: Oxaepam kinetics: effects of age and sex. J Pharmacol Exp Ther 215:86-91, Greenblatt DJ, Franke K, Shader RI: Analysis of loraepam and its glucuronide metabolite by electron-capture gas-liquid chromatography: use in pharmacokinetic studies of loraepam. J Chromatogr 146: , Greenblatt DJ, Schillings RT, Kyriakopoulos AA, Shader RI, Sisenwine SF, Knowles JA, Ruelius HW: Clinical pharmacokinetics of loraepam. I. Absorption and disposition of oral 14C-loraepam. CLIN PHARMACOL THER 20: , Homeida M, Halliwell M, Branch RA: Effects of an oral contraceptive on hepatic sie and antipyrine metabolism in premenopausal women. CLIN PHARMACOL THER 24: , Joni A, Bianchetti A, Prestini PE: Effect of contraceptive agents on drug metabolism. Eur J Pharmacol 7: , MacKinnon M, Sutherland E, Simon FR: Effects of ethinyl estradiol on hepatic microsomal proteins and the turnover of cytochrome P-450. J Lab Clin Med 90: , Orme MLE: The clinical pharmacology of oral contraceptive steroids. Br J Clin Pharmacol 14:31-42, Patwardhan RV, Desmond PV, Johnson RF, Schenker S: Impaired elimination of caffeine by oral contraceptive steroids. J Lab Clin Med 95: , Patwardhan R, Mitchell M, Johnson R, Schenker S: Induction of glucuronidation by oral contraceptive steroids (OCS). Clin Res 29:861A, 1981.