Characterization of cytochrome P450 (CYP) 2D6 drugs as substrates of human organic cation transporters and multidrug and toxin extrusion proteins.

Claudia Neul, Ute Hofmann, Elke Schaeffeler, Stefan Winter, Kathrin Klein, Kathleen M Giacomini, Michel Eichelbaum, Matthias Schwab, Anne T Nies

Journal: British journal of pharmacology 2021;178(6):1459-1474

PMID: 33434947

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Abstract

BACKGROUND AND PURPOSE

The metabolic activity of cytochrome P450 (CYP) 2D6 is highly variable and CYP2D6 genotypes insufficiently explain the extensive and intermediate metabolic phenotypes, limiting the prediction of drug response plus adverse drug reactions. Since CYP2D6 prototypic substrates are positively charged, the aim of this study was to evaluate the organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) as potential contributors to the variability of CYP2D6 hydroxylation of debrisoquine, dextromethorphan, diphenhydramine, perhexiline and sparteine.

EXPERIMENTAL APPROACH

OCT1/SLC22A1-, OCT2/SLC22A2-, OCT3/SLC22A3-, MATE1/SLC47A1-, and MATE2K/SLC47A2-overexpressing cell lines were used to investigate the transport of the selected drugs. Individuals from a study cohort, well defined with respect to CYP2D6 genotype and sparteine pharmacokinetics, were genotyped for the common OCT1 variants rs12208357 (OCT1-R61C), rs34130495 (OCT1-G401S), rs202220802 (OCT1-Met420del), rs34059508 (OCT1-G465R), OCT2 variant rs316019 (OCT2-A270S) and MATE1 variant rs2289669. Sparteine pharmacokinetics was stratified according to CYP2D6 and OCT1, OCT2 or MATE1 genotype.

KEY RESULTS

OCTs and MATE1 transport sparteine and debrisoquine with high affinity in vitro, but OCT- and MATE1-dependent transport of dextromethorphan, diphenhydramine and perhexiline was not detected. Sparteine and debrisoquine transport depends on OCT1 genotype; however, sparteine pharmacokinetics is independent from OCT1 genotype.

CONCLUSIONS AND IMPLICATIONS

Some drugs that are substrates of CYP2D6 are also substrates of OCTs and MATE1, suggesting overlapping specificities. Variability in sparteine hydroxylation in extensive and intermediate metabolizers cannot be explained by OCT1 genetic variants indicating presence of other factors. Dose-dependent toxicities of dextromethorphan, diphenhydramine and perhexiline appear to be independent from OCTs and MATEs.

Address: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany.; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany.; Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany.; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.; Institute of Human Genetics, University of California, San Francisco, California, USA.; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany.; Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany.; Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany.

DOI: 10.1111/bph.15370

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MeSH Terms: Cations, Cytochrome P-450 CYP2D6, Humans, Organic Cation Transport Proteins, Organic Cation Transporter 2, Pharmaceutical Preparations, Phenotype