Genetics in Pharmacokinetics?

To the Editor: Greer M. Murphy, Jr., M.D., Ph.D., et al. (1) evaluated the importance of the cytochrome P450 CYP2D6 polymorphism (pharmacokinetic effect) and a single nucleotide polymorphism (SNP) in the serotonin (5-HT) subtype 2A receptor locus (5-HTR_2A 102) as a pharmacodynamic effect on tolerance to the antidepressants paroxetine and mirtazapine. They described a major effect of the 5-HTR_2A 102 T/C SNP with significantly more discontinuations due to side effects in paroxetine-treated patients carrying the C/C allele. In mirtazapine-treated patients, no differences were found in the occurrence of side effects with respect to the 5-HTR_2A 102 genotype. Moreover, the CYP2D6 polymorphism obviously had no influence on the incidence of side effects in patients treated with either paroxetine or mirtazapine. The latter is surprising because mirtazapine and especially paroxetine are suggested substrates of CYP2D6. However, it is well documented that paroxetine inhibits its own metabolism, and at a final dose of 40 mg/day, there is no difference at all in the CYP2D6 activity (phenotype) between genotypical poor, intermediate, extensive, and ultra-rapid metabolizers (2, 3). This is nicely documented in the article by Dr. Murphy et al. by the plasma drug levels at day 28. At lower doses of paroxetine, when CYP2D6 is not completely inhibited, pharmacokinetic differences should become visible and are likely to affect the pharmacodynamics. The role of CYP2D6 in the pharmacokinetics of mirtazapine in vivo in patients is also questionable (4).

The results of Dr. Murphy et al. with respect to the 5-HT_2A receptor are of great clinical importance. However, my impression of the article was that Dr. Murphy and co-workers had chosen the wrong drugs at an improper dose to emphasize the importance of the 5-HTR_2A polymorphism (pharmacodynamics) against an enzyme polymorphism (pharmacokinetics).

There is a growing body of evidence that the consideration of pharmacokinetics can improve antidepressant or antipsychotic pharmacotherapy with regard to efficacy and safety. While reading the article, my clinical colleagues had the impression that pharmacokinetics is of little or no importance. However, the truth is that in many cases, genetics contribute only partially—and sometimes only to a small extent—to pharmacokinetics.