title: Impact of CYP2D6 intermediate metabolizer alleles on single-dose desipramine pharmacokinetics.
abstract: 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.
authors.affiliation: Department of Pharmacogenetics, Abbott Laboratories, Abbott Park, Illinois 60064-6217, USA.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Furman
authors.forename: David R
authors.initials: DR
authors.lastname: Grimm
authors.forename: Toby
authors.initials: T
authors.lastname: Mueller
authors.forename: Rhonda R
authors.initials: RR
authors.lastname: Holley-Shanks
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bertz
authors.forename: Laura A
authors.initials: LA
authors.lastname: Williams
authors.forename: Brian B
authors.initials: BB
authors.lastname: Spear
authors.forename: David A
authors.initials: DA
authors.lastname: Katz
mesh_terms: 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
chemical_list: D000929:Antidepressive Agents, Tricyclic; D019389:Cytochrome P-450 CYP2D6; D003891:Desipramine