Pharmacokinetics of 6-hydroxybuspirone and its enantiomers administered individually or following buspirone administration in humans

The objective of this study was to assess the pharmacokinetics of 6-hydroxybuspirone (6OHB) when given orally via three forms: racemate (BMS-528215), S-enantiomer (BMS-442606) and R-enantiomer (BMS-442608), versus following the administration of buspirone. A double-blind, randomized, four-period, four-treatment, crossover study balanced for residual effects in healthy subjects was conducted (n = 20). Subjects received single 10 mg doses of each compound in a randomized fashion with pharmacokinetics determined over a 24h period. There was a 4-day washout between each dosing period. All three forms of 6OHB (racemate, S-enantiomer and R-enantiomer) were well tolerated. There was interconversion between enantiomers. The dominant enantiomer was the S-enantiomer no matter which form of 6OHB was administered. All three forms of 6OHB produced approximately 2- to 3-fold greater exposure to total 6OHB than did buspirone. All three forms produced equal exposure to 1-(2-pyrimidinyl)-piperazine (I-PP) which was approximately 30% less than the I-PP exposure derived from buspirone administration. All three forms of 6OHB produced approximately 3-fold higher 6OH:1-PP:1-PP ratios and approximately 2.5-fold higher total 6OHB exposures than did buspirone administration. All compounds were well tolerated. There seemed to be no advantage of one of the enantiomers of 6OHB over the racemate. Therefore, the racemate was chosen for further clinical development. Copyright (C) 2007 John Wiley & Sons, Ltd.