A review of the literature indicates that the absolute oral bioavailability of exogenous melatonin in humans or in preclinical animal models has not been adequately characterized; hence, this study was undertaken. Pharmacokinetics of melatonin was studied in rats, dogs, and monkeys following intravenous and oral administrations, and the absolute oral bioavailability of melatonin was calculated from the area under the plasma concentration-time curve. The apparent elimination half-life of melatonin following an intravenous dose of 3 mg/kg (5 mg/kg in rats) was 19.8, 18.6, and 34.2 minutes, respectively, in rats, dogs, and monkeys. The dose normalized oral bioavailability of melatonin following a 10 mg/kg oral dose was 53.5% in rats, while it was in excess of 100% in dogs and monkeys. Further, bioavailability of melatonin following a 10 mg/kg intraperitoneal administration in rats was 74.0%, suggesting the lack of substantial first-pass hepatic extraction of melatonin in rats. However, the oral bioavailability of melatonin in dogs decreased to 16.9% following a 1 mg/kg oral dose, indicating dose-dependent bioavailability in dogs. In vitro permeability studies with CACO-2 cells suggest that melatonin is likely to be well absorbed in humans. In vitro metabolism studies with fresh liver slices from rats as well as human donors were conducted to compare the initial rates of metabolism of melatonin between the two species and the results suggest that the intrinsic clearance of melatonin in humans may be lower than that in rats.

This paper describes our studies aimed at the discovery of structurally distinct analogs of the cardioprotective KATP opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting compound 6, derived from the indole analog 4. showed good cardioprotective potency and excellent selectivity compared to 2 and the first-generation KATP opener cromakalim (1). The structure-activity studies indicate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its predecessor 6. The results described in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of KATP openers. Compound 3 is over 20- and 4000-fold more selective for the ischemic myocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the KATP blocker glyburide, indicating that the KATP opening is involved in its mechanism of cardioprotection. With its good oral bioavailability (47%) and plasma elimination half-life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.

An ion spray high-performance liquid chromatographic/tandem mass spectrometric (HPLC/MS/MS) method capable of determining the following six aminoglycosides in bovine kidney is presented: spectinomycin, hygromycin B, streptomycin, dihydrostreptomycin, gentamicin C complex and neomycin B. Tobramycin was used as an internal standard. This method uses an improved matrix solid-phase dispersion (MSPD) method for tissue extraction. A gradient HPLC separation was developed with mobile phases consisting of aqueous 20 mM pentafluoropropionic acid and acetonitrile. Protonated molecules served as precursor ions for collision-induced dissociation (CID) and three product ions were chosen for each analyte for selected reaction monitoring (SRM) where possible. A validation study was conducted for the confirmation of dihydrostreptomycin, neomycin B and four major components of the gentamicin C complex through SRM HPLC/MS/MS analysis of negative control, fortified and incurred bovine kidney samples. All of the samples analyzed could be confirmed with ion ratios within 15% of the daily mean of fortified standards and 90% of the samples had ion ratios within 10%. All compounds except spectinomycin could be detected (while monitoring three ions by SRM) in bovine kidney tissue at or below the regulatory level of concern. MSPD recoveries were acceptable with the exception of the 27% value observed for spectinomycin.

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