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A review of the influence of functional group modifications to the core scaffold of synthetic cathinones on drug pharmacokinetics

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Abstract

Rationale

The synthetic cathinones are a class of designer drugs of abuse that share a common core scaffold. The pharmacokinetic profiles of the synthetic cathinones vary based on the substitutions to the core scaffold.

Objectives

To provide a summary of the literature regarding the pharmacokinetic characteristics of the synthetic cathinones, with a focus on the impact of the structural modifications to the pharmacokinetics.

Results

In many, but not all, instances the pharmacokinetic characteristics of the synthetic cathinones can be reasonably predicted based on the substitutions to the core scaffold. Mephedrone and methylone are chemically alike and have similar Tmax and t1/2 in male rats. MDPV, a structurally distinct synthetic cathinone from mephedrone and methylone, has a lower Tmax and t1/2. Increasing the length of the alkyl chain on the α position of methylone, to produce pentylone, results in increased plasma concentrations and longer t1/2. Metabolism of the synthetic cathinones is reasonably predictable based on the chemical structure, and several phase I metabolites retain pharmacodynamic activity. CYP2D6 is implicated in the metabolism of all of the synthetic cathinones, and other P450s (CYP1A2, CYP2B6, and CYP2C19) are known to contribute variably to the metabolism of specific synthetic cathinones.

Conclusions

Continued research will lead to a better understanding of the pharmacokinetic changes associated with structural modifications to the cathinone scaffold, and potentially in the long range, enhanced overdose and addiction therapy. Additionally, the areas of polydrug use and pharmacogenetics have been largely overlooked with regard to synthetic cathinones.

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Abbreviations

3-MMC:

3-Methylmethcathinone

AUC0-∞ :

Area under the concentration versus time curve

BBB:

Blood-brain barrier

CLp/F:

Plasma clearance

Cmax :

Maximum concentration

CNS:

Central nervous system

COMT:

Catechol-O-methyltransferase

CYP:

Cytochrome P450

DAT:

Dopamine transporter

DEA:

Drug Enforcement Agency

IM:

Intermediate metabolizers

ip:

Intraperitoneal

iv:

Intravenous

MBI:

Mechanism-based inactivation

MDMA:

3,4-Methylenedioxymethamphetamine

MDPPP:

3′,4′-Methylenedioxy–α- pyrrolidinopropiophenone

MDPV:

3,4-Methylenedioxypyrovalerone

NET:

Norepinephrine transporter

NM:

Normal metabolizers

PGx:

Pharmacogenomics

po:

Per oral

RM:

Rapid metabolizers

sc:

Subcutaneous

SERT:

Serotonin transporter

t1/2,:

Half-life

Tmax :

Time of occurrence of maximum

UM:

Ultra-rapid metabolizers

VD/F:

Volume of distribution

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, Natural and Health Sciences, Manchester University, Fort Wayne, IN, 46845, USA

    Diane M. Calinski, David F. Kisor & Jon E. Sprague

  2. The Ohio Attorney General’s Center for the Future of Forensic Science, Bowling Green State University, Bowling Green, OH, 43403, USA

    Jon E. Sprague

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  1. Diane M. Calinski
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  2. David F. Kisor
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  3. Jon E. Sprague
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Correspondence to Jon E. Sprague.

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Calinski, D.M., Kisor, D.F. & Sprague, J.E. A review of the influence of functional group modifications to the core scaffold of synthetic cathinones on drug pharmacokinetics. Psychopharmacology 236, 881–890 (2019). https://doi.org/10.1007/s00213-018-4985-6

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