Br. J. clin. Pharmac. (1990), 29, 33-37
Single dose pharmacokinetics and pharmacodynamics of oral oxazepam during concomitant administration of propranolol and labetalol J. SONNE1*, M. D0SSING1, S. LOFT2, K. L. OLESEN', A. VOLLMER-LARSEN', M. A. VICTOR, 0. HAMBERG1 & H. THYSSEN1 'Departments of Medicine F, Gentofte University Hospital, and 2Pharmacology, University of Copenhagen, Denmark
1 The oral kinetics of oxazepam after a single 15 mg oral dose was investigated in six healthy volunteers before and during concomitant administration of the ,-adrenoceptor antagonists propranolol (80 mg) and labetalol (200 mg) (racemates). 2 A possible pharmacodynamic interaction between oxazepam and the 13-adrenoceptor antagonists was examined using a simple reaction time test (SRT) and by measurement of postural sway. 3 The kinetics of oxazepam were not affected significantly by propranolol or labetalol, although oxazepam and labetalol share the glucuronidation pathway. 4 The SRT was increased by combination of both 0-adrenoceptor antagonists with oxazepam, with the greatest increase after the coadministration of oxazepam with propranolol. Administration of the P-adrenoceptor antagonists alone had no significant effect. 5 Postural sway was affected significantly only by the combination of oxazepam and propranolol.
Keywords oxazepam propranolol labetalol pharmacokinetics pharmacodynamics glucuronidation Introduction is difficult to predict (Park, 1984). However, propranolol does not impair the clearance of lorazepam, a benzodiazepine biotransformed by glucuronidation (Ochs et al., 1984). We have investigated the kinetics of oral oxazepam during concomitant administration of racemic propranolol and labetalol. The latter shares the same metabolic pathway as the benzodiazepine oxazepam, being metabolised to inactive glucuronides (MacCarthy et al., 1983). A possible pharmacodynamic interaction between oxazepam and the two ,B-adrenoceptor antagonists was also investigated.
,B-adrenoceptor antagonists are often used in combination with other drugs with the potential for both pharmacodynamic and pharmacokinetic interactions. Several drugs having the ability to induce or inhibit drug metabolism have been shown to interact with 0-adrenoceptor antagonists sharing the same metabolic pathways (Park, 1984). 3-adrenoceptor antagonists themselves may act as inhibitors of oxidative biotransformation (Conrad et al., 1980; Greenblatt et al., 1978). The degree to which these findings may be extended to other oxidative metabolic pathways and to conjugation reactions
*Present address and correspondence: Dr J. Sonne, Department of Medicine, C, Herlev University Hospital, DK-2730 Herlev, Denmark
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J. Sonne et al.
Methods
Calculations
Four male and two female healthy volunteers took part in the study which was approved by the local ethics committee. They were aged between 26 and 38 years and none smoked or was on any medication.
Plasma oxazepam concentrations were analyzed by the ESTRIP program for kinetic studies (Brown et al., 1978). The area under the plasma concentration-time profile (AUC) was calculated by the linear trapezoidal approximation and the residual area to infinity was added. The oral clearance was calculated as dose divided by AUC and the volume of distribution by dividing clearance by the terminal elimination rate
Pharmacokinetic study Oxazepam kinetics were studied after the administration of 15 mg oxazepam (Serepax®, Ferrosan) by mouth following an overnight fast. A light breakfast was allowed 2 h after the dose. Venous blood samples were collected in heparinized tubes before and 15, 30, 45, 60, 90 min and 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after the dose of oxazepam. Plasma samples were stored at -20°C for subsequent analysis by an h.p.l.c. method (Sonne et al., 1988). Oxazepam kinetics were studied on two further occasions in random order after co-administration of propranolol or labetalol. Propranolol (80 mg) and labetalol (200 mg) were administered at bedtime on the evening before the study and again in the morning together with oxazepam. These studies were performed at an interval of at least 1 week.
constant.
Statistics Analysis of variance was performed using the Friedmann test and Wilcoxon's signed rank sum test was used to compare the single conditions (Wulff & Schlichting, 1988). 5% was chosen as the level of significance. Results No serious side effects were seen after the administration of the drugs. One subject had transient dizziness following both adrenoceptor antagonists and in all subjects these drugs lowered resting pulse rate by 15-25%.
Pharmacodynamic study
Kinetic study
These investigations were performed separate from the kinetic study. The subjects had one practice session with the testing procedures. The tests were then repeated six times at intervals of at least 1 week. After an overnight fast and 3 h before the tests two tablets were administered. One tablet was either placebo or oxazepam, the other either placebo, propranolol or labetalol. The order of treatments was randomised and the tablets were indistinguishable. A simple reaction time (SRT) was measured involving pressing a switch in response to an auditory stimulus. Immediately after the SRT a Romberg test was performed using a computerized force-plate system to measure postural stability (Janssen et al., 1982). A common sway vector was calculated from the transversal and sagittal sway and used as indication of sway. The higher the value, the greater the sway and postural imbalance. The times at which the tests of performance were made were chosen according to the time at which peak plasma concentrations of oxazepam were expected.
The median values of the pharmacokinetic parameters of oxazepam when given alone and after the coadministration of propranolol and labetalol are shown in Table I. The control oral clearance of oxazepam was 1.26 ml min-' kg-l (0.80-1.66) compared with 1.37 ml min-' kg-'I (0.92-1.61) after propranolol and 1.14 ml minkg-' (0.79-1.76) after labetalol (median; range). Neither the clearance nor the other kinetic variables were altered significantly by the administration of propranolol or labetalol.
Dynamic study Figures 1 and 2 indicate the results of the performance tests. Oxazepam alone and oxazepam with propranolol or labetalol affected the simple reaction time (SRT) significantly. No significant difference between the three drug combinations was found, although the most pronounced effect was seen following the concomitant administration of oxazepam and propranolol. Propranolol and labetalol alone did not prolong the SRT.
Oxazepam with propranolol and labetalol
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Table 1 Kinetic parameters of oxazepam (OXA) in six subjects with and without concomitant treatment with propranolol (PRO) and labetalol
(LAB): OXA
Peak plasma concentration (ng ml-1) Time of peak (h after dose) Terminal elimination half-life (h) Volume of distribution (I kg-1) Clearance (ml min- 1 kg-)
OXA + PRO
OXA + LAB
351
296
(210-567) 2.3 (1.7-2.8) 6.0 (5.446.2) 0.48 (0.39-0.80) 1.26
(220-513) 2.1 (1.2-3.0)
319 (230-581)
5.6
(5.1-6.5) 1.37
(5.1-7.2) 0.65 (0.36-0.75) 1.14
(0.92-1.61)
(0.79-1.76)
0.66
(0.40-0.78)
(0.80-1.66)
2.3
(1.0-3.0) 5.7
Values are median and range
Reaction time (ms) 600 a
Placebo -
800 I
Oxazepam Labetalol -
Propranolol -
Oxazepam + propranolol-
Oxazepam + labetalol -
_~ Subject 1
Subject 2
Subject 3
9 Subject 5 C] Subject 6 s Subject 4 Figure 1 Reaction time in six subjects after the administration of placebo, oxazepam (15 mg), propranolol (80 mg), labetalol (200 mg) and combinations of oxazepam and propranolol or labetalol.
Postural sway during the Romberg test was
significantly increased by the combined administration of oxazepam and propranolol, whereas the administration of oxazepam, propranolol and labetalol alone or oxazepam with labetalol had no effect. Discussion The administration of two 80 mg doses of propranolol and two 200 mg doses of labetalol did
not affect the kinetics of oral oxazepam. In the case of propranolol this was not surprising, since propranolol has been shown to have no effect on the clearance of lorazepam which, like oxazepam, is mainly glucuronidated (Ochs et al., 1984). Labetalol, on the other hand, shares the same metabolic pathway as oxazepam and an interaction might be anticipated. However, a common metabolic fate is not necessarily a good determinant of a drug interaction. Although dissimilar in their metabolism propranolol and labetalol both decrease the clearance of the
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J. Sonne et al.
Placebo
..
200
noo
400(>f.. '.2t
200
300
400
200
300
.....I-a
...
Oxazepam 2 LabetakA*
Propranolol Oxazepam + propranot
Oxazepam +labetalol
-
0
100
-S""tXm SuCt 4
2
400
500
600
700
pbj~~~~~~~~~~ect3
2 8 bje 6.
pject 6
Figure 2 Postural sway in six subjects after the administration of placebo, oxazepam (15 mg), propranolol (80 mg), labetalol (200 mg) and combinations of oxazepam and propranolol or labetalol.
oxidatively metabolised model drug antipyrine (Daneshmend & Roberts, 1982). The interpretation of interaction studies is also complicated by the existence of different isozymes catalyzing the same reactions. Thus the lack of inhibition of oxazepam by labetalol might be explained by their metabolism by different UDP-glucuronyltransferases. The results of the dynamic study indicated that oxazepam and its combination with either of the P-adrenoceptor antagonists affected the simple reaction time, but differences between the treatments were not significant statistically. The finding that propranolol and labetalol alone did not prolong the reaction time was in contrast to the results of other studies on the central effects of single dose propranolol (Laudauer et al., 1974; Ogle & Turner, 1974; Ogle et al., 1976; Salem & McDevitt, 1984). Conflicting results may be ascribed to differences in dose, lower doses tending to produce greater effects in performance tests (Salem & McDevitt, 1984). In the present study the use of a small sample size must also be taken into consideration. File & Lister (1985) found that single doses of propranolol and lorazepam increased simple reaction time. Lorazepam is chemically and metabolically similar to oxazepam.
In the Romberg test a dynamic interaction was found between oxazepam and propranolol. Propranolol alone did not affect postural sway, a finding that was also reported by Lidegaard et al. (1984) with equivalent doses. The fact that we were unable to demonstrate any effect with oxazepam alone might be explained by the doseresponse relationship, the oxazepam dose being too small (Swift et al., 1984). In conclusion, no kinetic interaction between oxazepam and the ,-adrenoceptor antagonists propranolol and labetalol could be demonstrated after the administration of single doses of oxazepam. A pharmacodynamic interaction between oxazepam and propranolol was found on postural sway. Simple reaction time was affected by oxazepam and all drug combinations, but with the greatest increase after concomitant administration of oxazepam and propranolol. The Lundbeck Foundation kindly donated the h.p.l.c. equipment. This work was supported by grants from the Jacob Madsen and Olga Madsen Foundation. The technical skill of Ms Hjerpsted is greatly appreciated. Dr E. C. Janssen and chief psychologist Ulla Danielsen are thanked for their help with the performance tests.
Oxazepam with propranolol and labetalol
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Ochs, H. R., Greenblatt, D. J. & Verburg-Ochs, B. (1984). Propranolol interactions with diazepam, lorazepam and alprazolam. Clin. Pharmac. Ther., 36, 451-455. Ogle, C. W. & Turner, P. (1974). The effects of oral doses of oxprenolol and of propranolol on CNS function in man. J. pharmac. clin., 1, 256-261. Ogle, C. W., Turner, P. & Markomihelakis, H. (1976). The effects of high doses of oxprenolol and of propranolol on pursuit rotor performance, reaction time and critical flicker frequency. Psychopharmacologica (Berl.), 46, 295-299. Park, B. K. (1984). Prediction of metabolic drug interactions involving ,B-adrenoceptor drugs. Br. J. clin. Pharmac., 17, 3S-10S. Salem, S. A. M. & McDevitt, D. G. (1984). Central effects of single oral doses of propranolol in man. Br. J. clin. Pharmac., 17, 31-36. Sonne, J., Loft, S., D0ssing, M., Vollmer-Larsen, A., Olesen, K. L., Victor, M., Andreasen, F. & Andreasen, P. B. (1988). Bioavailability and pharmacokinetics of oxazepam. Eur. J. clin. Pharmac., 35, 385-389. Swift, C. G. (1984). Postural instability as a measure of sedative drug response. Br. J. clin. Pharmac., 18, 87S-90S. Wulff, H. & Schlichting, P. (1988). MEDSTAT. Statistical program for the analysis of the results of controlled therapeutic trials and other types of clinical research. Version 2.1. Copenhagen: Astra.
(Received 17 May 1989, accepted 12 September 1989)