title: Linear pharmacokinetics of 3,4-methylenedioxypyrovalerone (MDPV) and its metabolites in the rat: relationship to pharmacodynamic effects.
abstract: 3,4-Methylenedioxypyrovalerone (MDPV) is a commonly abused synthetic cathinone in the United States and is associated with dangerous side effects. MDPV is a dopamine transporter blocker that is 10-fold more potent than cocaine as a locomotor stimulant in rats. Previous in vitro and in vivo metabolism studies identified 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4-hydroxy-3-methoxypyrovalerone (4-OH-3-MeO-PV) as the two primary MDPV metabolites. This study examined MDPV pharmacokinetics and metabolism, along with associated pharmacodynamic effects in rats receiving 0.5, 1.0 and 2.0 mg/kg subcutaneous (s.c.) MDPV. Blood was collected by an indwelling jugular catheter before dosing and at 10, 20, 30, 60, 120, 240 and 480 minutes thereafter. Plasma specimens were analyzed by liquid chromatography coupled to high-resolution tandem mass spectrometry. Maximum concentrations (Cmax ) and area-under-the-curve (AUC) for MDPV and two metabolites increased proportionally with administered dose, showing linear pharmacokinetics. MDPV exhibited the highest Cmax at all doses (74.2-271.3 μg/l) and 4-OH-3-MeOH-PV the highest AUC (11 366-47 724 minutes per μg/l), being the predominant metabolite. MDPV time to Cmax (Tmax ) was 12.9-18.6 minutes, while 3,4-catechol-PV and 4-OH-3-MeO-PV peaked later with Tmax 188.6-240 minutes after s.c. dosing. Horizontal locomotor activity (HLA) and stereotypy correlated positively with plasma MDPV concentrations, while HLA correlated negatively with MDPV metabolites. These results suggest that the parent compound mediates motor stimulation after systemic MDPV administration, but additionally, metabolites may be inhibitory, may not be active or may not pass the blood brain barrier.
authors.affiliation: Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Anizan
authors.affiliation: Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Concheiro
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Lehner
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Mohammad O
authors.initials: MO
authors.lastname: Bukhari
authors.affiliation: Drug Design and Synthesis Section, Intramural Research Program, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, MD, USA.|On leave from the Medicinal Chemistry Group, Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Drug Design and Synthesis Section, Intramural Research Program, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Huestis
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D015198:Designer Drugs / Q000493:pharmacokinetics / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011619:Psychotropic Drugs / Q000493:pharmacokinetics* / Q000494:pharmacology; D011759:Pyrrolidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D000094982:Synthetic Cathinone
chemical_list: D052117:Benzodioxoles; D015198:Designer Drugs; D018765:Dopamine Uptake Inhibitors; D011619:Psychotropic Drugs; D011759:Pyrrolidines; D000094982:Synthetic Cathinone
keywords: MDPV; PK/PD; bath salts; designer drugs; metabolites; synthetic cathinones