Impact of CYP2D6 intermediate metabolizer alleles on single-dose desipramine pharmacokinetics.
This study utilized cytochrome P450 2D6 (CYP2D6) genotypes to explain variability of desipramine pharmacokinetics in a cohort of non-poor metabolizer individuals. In an interaction study utilizing desipramine as a probe, genotyping for the CYP2D6*3, *4, *5 and *6 alleles was used to screen out CYP2D6 poor metabolizers. Individuals were categorized according to these and additional alleles (CYP2D6*2, *9, *10, *17, *41 and x2). Genotypes of individuals heterozygous for two or three of *2, *17 and *41 alleles were confirmed by molecular haplotyping. Pharmacokinetic parameters of desipramine were analysed according to CYP2D6 category. Molecular haplotyping was necessary to definitively categorize four of 16 individuals. A subject who had unusually high plasma elimination half-time, exposure and metabolic ratios carried an intermediate metabolizer (IM) *9 allele in combination with a non-functional allele. This combination has a population frequency of less than 1 : 200. Individuals with *1/*1, *1/*2 and *2/*2 genotypes had lower than average plasma elimination half-time, exposure and metabolic ratios. For desipramine, additional genotyping of CYP2D6 IM alleles helped define subgroups of the CYP2D6-positive cohort. This suggests that genotyping for IM alleles will aid in interpretation of clinical trials involving CYP2D6 substrates. Due to the diversity of IM alleles, molecular haplotyping may be necessary to fully characterize CYP2D6 genotype-phenotype relationships.
Furman
Katherine D
KD
Department of Pharmacogenetics, Abbott Laboratories, Abbott Park, Illinois 60064-6217, USA.
Grimm
David R
DR
Mueller
Toby
T
Holley-Shanks
Rhonda R
RR
Bertz
Richard J
RJ
Williams
Laura A
LA
Spear
Brian B
BB
Katz
David A
DA
D000483:Alleles; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics*; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003891:Desipramine / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D010641:Phenotype
D000929:Antidepressive Agents, Tricyclic; D019389:Cytochrome P-450 CYP2D6; D003891:Desipramine