The pharmacokinetics of racemic MDPV and its (R) and (S) enantiomers in female and male rats

Abstract

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 (Vdss) 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 (AUCinf) 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.

Cardiovascular effects of 3,4-methylenedioxypyrovalerone (MDPV) in male and female Sprague-Dawley rats

“…Previous findings from our group show that there are sex-dependent differences in MPDV pharmacokinetics (Hambuchen et al, 2017a). Indeed, male SD rats have a greater bioavailability of MDPV after IP administration than female SD rats (Fig.…”

“…In a previous study by Hambuchen et al (2017a), bioavailability of 3 mg/kg MDPV is shown to be significantly greater for males than females (Fig. 5A).…”

“…Locomotor activity were analyzed as described above and locomotor activity counts were summed cumulatively every 2 h during the binge. Predicted MDPV serum concentration-time data during binge dosing was simulated using Phoenix WinNonlin software (V6.4, Certara USA, Princeton, NJ) and pharmacokinetic parameters derived from previous 3 mg/kg IP MDPV pharmacokinetics studies in male and female SD rats (Hambuchen et al, 2017a). These predicted concentration-time curves were then compared to the observed MDPV serum concentrations collected at 2 h after the last binge dose.…”

“…Several studies report the pharmacokinetic properties of MDPV in rats after different routes of administration. In male rats, the elimination half-life of MDPV is reported at 1-2 h among several studies using either SC, intraperitoneal (IP), or intravenous (IV) administration (Anizan et al, 2016;Baumann et al, 2016;Hambuchen et al, 2017a;Horsley et al, 2018). A study of the pharmacokinetics of MDPV after IP dosing of males and female rats (Hambuchen et al, 2017a).…”

Detrimental effects of the ‘bath salt’ methylenedioxypyrovalerone on social play behavior in male rats

“…These results suggest that the acute effects of MDPV on social play behavior are comparable to the effects of other psychostimulants, which are also abused in social settings, such as amphetamine, methylphenidate, or cocaine, that also exert play-suppressant effects in male rats [14,24,40]. Importantly, sex-dependent differences in the effects of MDPV [54][55][56] and in the structure and intensity of social play behavior [23] have been documented. Therefore, investigating the effects of MDPV on social play behavior in female rats, and the neural mechanisms involved, is an intriguing issue which deserves further investigation.…”