Effects of Polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on Trimipramine Pharmacokinetics

Abstract

Little is known about the impact of cytochrome P450 polymorphisms on the metabolism of trimipramine, which is still widely used as antidepressant due to its positive effect on sleep patterns. A single oral dose of 75 mg trimipramine was given to 42 healthy volunteers selected according to their CYP2D6, CYP2C19, and CYP2C9 genotypes. The reference group included 8 subjects with homozygous active wild-type genotypes of all 3 enzymes (EM). This group was compared with 7 intermediate (IM) with 1 and 7 poor metabolizers (PM) with zero active alleles of CYP2D6 and CYP2C19, respectively, and with 4 subjects with the genotype CYP2C9*3/*3. Pharmacokinetics of trimipramine and its demethylated metabolite strongly depended on the CYP2D6 genotype. Median oral clearance of trimipramine was 276 L/h (range 180-444) in the reference group but only 36 L/h (range 24-48) in CYP2D6 PMs (P < 0.001). These differences could only be explained by an effect of CYP genotypes on both parameters, systemic clearance and bioavailability, the latter being at least 3-fold higher in CYP2D6 PMs than in the reference group. The desmethyltrimipramine area under the concentration-time curve was 40-fold greater in CYP2D6 PMs than in the reference group (1.7 vs. 0.04 mg/L x h in EMs), but below the quantification limit in most carriers of deficiencies of CYP2C19 or CYP2C9. This indicates that both CYP2C enzymes contribute to the demethylation of desmethyltrimipramine and CYP2D6 to further metabolism.

Allele-Specific Change of Concentration and Functional Gene Dose for the Prediction of Steady-State Serum Concentrations of Amitriptyline and Nortriptyline in CYP2C19 and CYP2D6 Extensive and Intermediate Metabolizers

“…c Significant difference (P Ͻ0.05). (14,33,34 ). To date, the focus has been on finding correlations between CYP2D6 genotypes and the four populations that can be differentiated by several test drugs.…”

“…In preselected populations designed to detect CYP2D6-related pharmacokinetic differences (33,34 ), trimipramine and doxepin clearance differed significantly between carriers of two or only one functional allele. However, alleles with reduced function (*9, *10, and *41) were not considered, and single-dose studies in highly controlled populations of volunteers may not predict the real therapeutic relevance of genomic variations when patients are treated chronically with drugs because of nonlinear kinetics, tolerance, and/or compensatory homeostatic mechanisms.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…As indicated in section II.A., the metabolism of this class is complex, with CYP2C19 being involved in the demethylation of the tertiary amines (Fig. 1) Koyama et al, 1997;Venkatakrishnan et al, 1998;Kirchheiner et al, 2003d). The tertiary TCAs all seem to behave similarly with respect to the CYP2C19 polymorphism Kramer Nielsen et al, 1994;Eap et al, 2000;Yokono et al, 2001;Kirchheiner et al, 2003d).…”

“…1) Koyama et al, 1997;Venkatakrishnan et al, 1998;Kirchheiner et al, 2003d). The tertiary TCAs all seem to behave similarly with respect to the CYP2C19 polymorphism Kramer Nielsen et al, 1994;Eap et al, 2000;Yokono et al, 2001;Kirchheiner et al, 2003d). In CYP2C19 PMs, elevated amitriptyline (1.4-to 1.8-fold) and reduced nortriptyline concentrations (to 40-80%) occur.…”

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

“…59,67 Clinical impact of pharmacogenetic testing for polymorphic drug metabolism Although differences in the pharmacokinetic parameters due to polymorphic metabolism are relatively well characterized with a surprisingly good betweenstudy concordance (Tables 2 and 3, and Figure 1), the impact of those variations on therapeutic outcomes and incidence and severity of adverse drug reactions are not as well documented. Few studies provide quantitative data on adverse drug reactions.…”