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BMS-214778 is a novel melatonin receptor agonist that may be a useful treatment for sleep disorders that result from disruption of circadian rhythms. Pharmacokinetic studies following intravenous and oral administration and 1 month oral steady-state studies were carried out in rats and monkeys. Rat brain was analyzed for BMS-214778 to determine the extent of its penetration from plasma. Equilibrium dialysis was employed to determine the extent of binding of [(14)C]-BMS-214778 to rat, monkey, and human sera proteins. In vitro metabolism studies with BMS-214778 in rat, monkey, and human liver homogenate preparations (S-9), with monkey and human liver slice preparations, and with pooled human liver microsomes were performed and the incubates analyzed for potential metabolites. Recombinant microsomes expressing specific human cytochrome P(450) (CYP) enzymes were employed to identify possible human metabolic pathways. BMS-214778 showed a high hepatic extraction and high degree of tissue distribution. BMS-214778 also displayed non-linear oral pharmacokinetics. Systemic exposures following oral doses in rats and monkeys increased more than proportionally to the increment in dose. Loss of systemic exposure to BMS-214778 upon chronic oral dosing was observed in male rats where exposure was one-half to two-thirds compared to a single dose, while modest decreases in exposure were observed upon chronic dosing in both sexes of monkey. This was suggestive of induction of BMS-214778 clearance and/or excretion mechanisms. BMS-214778 distributed from the plasma to brain in the rat (mean +/- SD brain:plasma ratio of 0.9 +/- 0.1, N = 3). [(14)C]-BMS-214778 was moderately bound to serum proteins (<91% bound) in all species examined. In vitro metabolism of BMS-214778 was mostly by hydroxylation and dehydrogenation, with CYP1A1, 1A2, 2D6, and 2C9 being the most likely isoforms to be involved in its metabolism in humans., (Copyright 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:760-772, 2003)

A chiral high-performance liquid chromatographic assay for the separation of the four stereoisomers of labetalol, an antihypertensive, in biological fluids has been developed. Baseline separation of the isomers was achieved using an alpha 1-acid glycoprotein stationary phase. No interference from endogenous substances was observed following extraction from various biological fluids obtained from pregnant (ewe and fetus) and non-pregnant sheep. The concentration of the individual isomers of labetalol was determined by first measuring the total concentration of racemic labetalol obtained from an achiral assay followed by reassay of each sample by the chiral method after which, by using the estimate of the percentage of each individual isomer, the individual concentration of each of the four isomers was determined. The mobile phase was 0.02 M phosphate buffer containing 0.015 M tetrabutylammonium phosphate. The pH of the mobile phase was adjusted to 7.10. The detector was set at an excitation wavelength of 230 nm and emission wavelength of 400 nm to monitor the nascent fluorescence intensity of the isomers of labetalol. The limit of detection of the individual isomers was 0.15 ng (0.6 ng of injected racemic labetalol). The assay was linear over the range 0.6-15.0 ng of labetalol (injected) with the intra- and inter-day mean coefficients of variation being less than 9.0 and 6.0%, respectively. Application of the assay in the study of pharmacokinetics of the stereoisomers of labetalol in sheep following administration of racemic labetalol has been demonstrated.

A rapid and sensitive microbore high-performance liquid chromatographic (HPLC) assay is reported for the quantitation of labetalol, an anti-hypertensive agent, in small volumes (250 microliters) of biological fluids (viz., maternal plasma, fetal plasma, amniotic fluid and fetal tracheal fluid) obtained from the chronically instrumented pregnant sheep. Labetalol was extracted from the samples using ethyl acetate and then partitioned into dilute phosphoric acid. Chromatography was performed on a microbore HPLC system using a 2.1 mm I.D. C18 column and detection was accomplished by a low-dispersion fluorescence detector designed for trace analysis. The drug was well separated from endogenous substances in all biological fluids sampled. The calibration curves were linear for all fluids over the range of study with mean coefficients of variation consistently below 5%. Quantitation was possible down to approximately 30 pg of labetalol injected (approximately 1.6 ng/ml in plasma using 250 microliters).