CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6-serotonin-dopamine crosstalk revisited.

OBJECTIVES: Hyperprolactinemia is a common side effect of first-generation antipsychotics mediated by antagonism of dopaminergic neurotransmission in the pituitary. Most first-generation antipsychotics are metabolized by CYP2D6 in the liver. Further, CYP2D6 is expressed in the human brain as a 5-methoxyindolethylamine O-demethylase potentially contributing to regeneration of serotonin from 5-methoxytryptamine. As dopaminergic neurotransmission is subject to regulation by serotonin, CYP2D6 may exert a nuanced (serotonergic) influence on dopaminergic tone in the pituitary. CYP2D6*10 is an allele associated with reduced enzyme function and occurs in high frequency (about 50%) in Asians. We prospectively evaluated significance of CYP2D6 genetic variation for prolactin response to perphenazine (a model first-generation antipsychotic) in Asians. METHODS: A single oral dose of perphenazine (0.1 mg/kg) or placebo was administered to 22 medication-free nonsmoker healthy male Chinese-Canadian volunteers, following a double-blind within-subject randomized design. Blood samples were drawn at baseline and 2, 3, 4, 5 and 6 h after drug administration. RESULTS: In volunteers with CYP2D6*10/CYP2D6*10 genotype, the mean area under curve (AUC0-6) for perphenazine concentration was 2.9-fold higher than those who carry the CYP2D6*1 allele (P<0.01). Notably, volunteers homozygous for CYP2D6*10 exhibited a significant reduction (66%) in mean pharmacodynamic tissue sensitivity as measured by the (prolactin-AUC0-6/perphenazine-AUC0-6) ratio (P=0.02). CONCLUSIONS: CYP2D6 genotype is a significant contributor to perphenazine concentration in Chinese-Canadians. Importantly, prolactin response, when normalized per unit perphenazine concentration, appears to be blunted in volunteers homozygous for CYP2D6*10. We suggest that CYP2D6 genetic variation may potentially influence pharmacodynamic tissue sensitivity in the pituitary, presumably through disposition of an endogenous substrate (e.g. 5-methoxytryptamine).

Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes.

AIMS: To investigate pharmacokinetics of the enantiomers of citalopram (CT) and its metabolites desmethylcitalopram (DCT) and didesmethylcitalopram (DDCT) in Swedish healthy volunteers in relation to CYP2C19 and CYP2D6 geno- and phenotypes. METHODS: Racemic CT was given for seven days to panels with different genotypes and the following mephenytoin (Me) and debrisoquine (De) hydroxylation phenotypes: EMDe/EMMe, PMDe/EMMe, EMDe/PMMe (n = 6 in all groups), and one PMDe/PMMe subject. Blood sampling was carried out during day 7, and all urine was collected for 12 h after the last dose of CT. RESULTS: The AUC of S-CT was significantly higher in the EMDe/PMMe panel compared to the EMDe/EMMe and PMDe/EMMe panels (P < 0.05), whereas the AUC of R-CT did not differ between the panels. Similar differences, although they did not reach statistical significance, were noted for S-DCT and R-DCT. The enantiomers of DDCT were not quantifiable in PMDe, and there was no difference in DDCT enantiomer concentrations between the other two panels. A PMDe/PMMe subject stopped taking CT after five days due to severe adverse effects. Based on two time points, this subject had a very long CT half-life of 95 h. The value of 1.0 for the S/R ratio of the CT trough in this subject was similar to the mean S/R CT trough ratio of the EMDe/PMMe panel, but higher than the S/R CT ratio of the EMDe/EMMe panel (0.56; 95% CI 0.49-0.63) and the PMDe/EMMe panel (0.44; 95% CI 0.31-0.57). Thus the latter two phenotypes eliminated S-CT more rapidly via CYP2C19. An adverse effect described as an 'alcohol hangover' feeling was reported by one subject from each of the three panels. These individuals had the highest concentrations of both CT enantiomers. CONCLUSIONS: The AUC of S-, but not R-(CT) was found to be significantly higher in PM of mephenytoin compared to EMs, PMs may need a lower dosage of CT.

A screening study on the liability of eight different female sex steroids to inhibit CYP2C9, 2C19 and 3A4 activities in human liver microsomes.

The aim of this study was to screen the inhibitory potential of different clinically used oestrogen and progestin hormones on CYP2C9, 2C19 and 3A4 activities in human liver microsomes. The degree of inhibition by desogestrel, 3-ketodesogestrel, 17-beta-oestradiol, gestodene, aethinyloestradiol, medroxyprogesterone acetate, norethisterone or L-norgestrel were studied at 100 microM on losartan oxidation (CYP2C9), R-omeprazole 5'-hydroxylation (CYP2C19) and R-omeprazole sulphoxidation (CYP3A4) with a 10-min preincubation with NADPH in human liver microsomes prepared from 6 individual genotyped donor livers. Aethinyloestradiol was found to be a potent inhibitor (55% mean inhibition; 95% CI 32% to 79%) of losartan oxidation (CYP2C9) and R-omeprazole 5-hydroxylation (70%; 63% to 77%) (CYP2C19), while it had little effect on R-omeprazole sulphoxidation (CYP3A4) activity. 17-beta-Oestradiol did not produce significant inhibition on any of the studied enzyme activities. Of the progestin hormones studied, gestodene and 3-ketodesogestrel were potent inhibitors of CYP2C19 (57%; 47% to 67% and 51%; 29% to 45%) and CYP3A4 (45%; 30% to 59% and 40%; 19% to 62%), but had little effect on the CYP2C9 activity. In addition, medroxyprogesterone acetate was found to inhibit CYP2C9 (55%; 45% to 65%), while not having significant effect on 2C19 or 3A4. In conclusion, the liability of clinically used female sex steroids to inhibit CYP2C9, 2C19 and 3A4 activities in human liver microsomes is very distinctive and these differences among both the oestrogen and progestin hormones may, at least in part, explain the variable results from clinical trials examining inhibitory effects of hormone replacement therapy and oral contraceptives on drug metabolism.