Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype.
OBJECTIVE
Recently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O-demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes.


METHODS
Norwegians of Caucasian origin were screened for their CYP2D6 genotype on the LightCycler (Roche Diagnostics, Mannheim, Germany) by melting-curve analysis of allele-specific fluorescence resonance energy transfer probes hybridized to polymerase chain reaction-amplified deoxyribonucleic acid. The first 5 individuals identified with genotypes corresponding to a homozygous extensive, heterozygous extensive, or homozygous poor CYP2D6-metabolizing phenotype, respectively, were voluntarily enrolled in the pharmacokinetic study. The participants received diltiazem, 120 mg, as a single oral dose, and plasma samples were collected up to 24 hours after administration. Plasma samples were purified by solid phase extraction. Diltiazem and 7 phase I metabolites were analyzed by liquid chromatography-mass spectrometry.


RESULTS
The pharmacokinetics of diltiazem was not significantly different between the subgroups. However, the systemic exposure of the pharmacologically active metabolites desacetyl diltiazem and N-demethyldesacetyl diltiazem was > or = 5 times higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (P <.01).


CONCLUSIONS
CYP2D6 activity does not have a major impact on the disposition of diltiazem. In contrast, desacetyl diltiazem and N-demethyldesacetyl diltiazem are markedly accumulated in individuals expressing a deficient CYP2D6 phenotype. Because these metabolites exhibit pharmacologic properties of possible importance, individual CYP2D6 activity might be an aspect to consider in the clinical use of diltiazem.
Molden
Espen
E
Department of Pharmacology and Pharmaceutical Analysis, School of Pharmacy, University of Oslo, Norway. espen.molden@farmasi.uio.no
Johansen
Per Wiik
PW
Bøe
Grethe Helen
GH
Bergan
Stein
S
Christensen
Hege
H
Rugstad
Hans Erik
HE
Rootwelt
Helge
H
Reubsaet
Leon
L
Lehne
Gustav
G
D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male
D002121:Calcium Channel Blockers; C037769:deacetyldiltiazem; D019389:Cytochrome P-450 CYP2D6; D004110:Diltiazem