Journal
DRUG AND ALCOHOL DEPENDENCE
Volume 179, Issue -, Pages 347-354Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.drugalcdep.2017.07.011
Keywords
(3,4)-methylenedioxypyrovalerone; Chirality; Pharmacokinetics; Bioavailability; Behavior; Rat sex
Categories
Funding
- NIH National Institute on Drug Abuse [R01 DA039195]
- National Center for Advancing Translational Sciences [ULITR000039]
- Arkansas Biosciences Institute (the major research component of the Arkansas Tobacco Settlement Proceeds Act)
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Background: These studies investigated the serum pharmacokinetic (PK) profile of racemic (3,4)-methylenedioxypyrovalerone [(R,S)-MDPV)] and its (R)- and (S)-enantiomers in female and male Sprague Dawley rats. Methods: Intravenous (R,S)-MDPV (3 and 5.6 mg/kg) and single enantiomer of (R)- and (S)-MDPV (1.5 mg/kg) were administered to both sexes for PK studies. Intraperitoneal (ip) bioavailability was determined at 3 mg/kg (R,S)-MDPV. Locomotor activity studies were conducted after ip treatment with saline and 0.3-5.6 mg/kg of (R,S)-MDPV. Results: PK values after iv (R,S)-MDPV showed a significant (p < 0.05) sex-dependent differences in the volume of distribution at steady state (Vd) for (R)- and (R,S)-MDPV at both (R,S)-MDPV doses. The female S/R enantiomeric ratios for area under the concentration time curve (AUC,nf) and clearance were significantly lower and higher, respectively, than values determined in males. Importantly, there was no evidence of in vivo inversion of (R)-MDPV or (S)-MDPV to its antipode. There were, however, significant sex-dependent differences in volume of distribution after administration of the (R)-enantiomer. Bioavailability studies of ip (R,S)-MDPV showed greater variability and significantly greater bioavailability in male rats. Accordingly, there was a significantly greater maximal distance traveled measurement in male rats at a 3.0 mg/kg dose. Conclusion: PK sex differences in (R,S)-MDPV and enantiomers were most apparent in volume of distribution, which could be caused by differences in drug blood and tissue protein binding. The increased magnitude and variance in ip bioavailability in male compared to female rats could lead to sex-dependent differences in the pharmacological action caused by active enantiomer (S)-MDPV.
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