Pharmacokinetics and bioavailability of benperidol were determined in 13 schizophrenic patients after acute administration of 6 mg benperidol as an intravenous (i.v.) bolus injection, orally as liquid, and orally as tablets using a partially randomized cross-over design. Drug plasma levels were determined by high performance liquid chromatography with electrochemical detection and subjected to model independent pharmacokinetic analyses. After i.v. dosing the geometric means (mean-g) were 3.2 min for the distribution half-life, 5.80 h for the elimination half-life (t1/2 beta), 4.21 l/kg for the distribution volume, 7.50 h for the mean residence time (MRT), and 0.50 l/(h*kg) for the clearance. After oral administration as liquid and as tablet mean-g data for the time lag until the first appearance of measurable plasma concentrations were 0.33 and 1.1 h, mean-g t1/2 beta values were 5.5 and 4.7 h, respectively, mean-g tmax data were 1.0 h and 2.7 h, mean-g MRT values were 8.44 and 8.84 h, and mean-g Cmax maxvalues were 10.2 and 7.3 ng/ml. Differences between liquid and tablet administration were statistically significant for time lag, tmax, and Cmax. Mean-g absolute bioavailabilities were computed as 48.6% after liquid and 40.2% after tablet administration respectively. All parameters studied exhibited large intersubject variation. The plasma concentrations of the presumed metabolite "reduced benperidol" were found to be very low.
The metabolism of the non-psychotropic cannabinoid (3R, 4R)-A' (7)-tetrahydrocannabinol(1) (=A' (7)-THC) was investigated in a rat liver microsomal preparation. The metabolites obtained from the incubation mixture were separated, purified and identified by 'H-NMR. spectroscopy and combined gas-liquid chromatography/ mass spectrometry. Metabolites 3-10 are derived from A'(7)-THC (1) by monohydroxylation in the isoprenoid moiety or the side chain of the molecule. Metabolites 11-16 are hydroxylated in the isoprenoid ring and the side chain simultaneously. The third group, metabolites 18-22, is derived from the 1,7epoxide 17 by hydrolysis of the oxirane ring, three of these metabolites bearing additional hydroxyl-groups in the isoprenoid part or the side chain. The mass spectra of the metabolites are discussed in detail and a new rule for the fragmentations of tetrahydrocannabinols is presented.
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