Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients

Aims This study was carried out to evaluate the influence of CYP2D6 genotyp e on the steady state plasma concentrations of haloperidol and reduced halo peridol in Korean schizophrenic patients. Methods One hundred and twenty Korean schizophrenic patients treated with v arious, clinically determined, doses of haloperidol (range 3-60, median 20 mg day(-1)) during monotherapy were recruited. CYP2D6 genotypes were determ ined by analysis of the CYP2D6*10 allele using allele-specific PCR and the CYP2D6*5 allele by long-PCR. Steady state plasma concentrations of haloperi dol and reduced haloperidol were analysed by h.p.l.c. Results Twenty-three (19.2%), 60 (50.0%), 1 (0.8%), 33 (27.5%) and 3 patien ts (2.5%) possessed the CYP2D6 genotypes *1/*1, *1/*10, *1/*5, *10/*10 and *10/*5, respectively. The allele frequencies of CYP2D6*1, *10 and *5 were 4 4.6%, 53.8% and 1.7%, respectively. Significant relationships between dose and plasma concentrations of haloperidol (linear; r(2)=0.60, P<0.0001) and reduced haloperidol (quadratic equation; r(2)=0.67) were observed. Overall, the concentrations normalized for dose (C/D) of haloperidol were significa ntly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups (one-way ANOVA; P=0.028). No significant differences between the genotype g roups were found with respect to the C/D of reduced haloperidol (P=0.755). However, in patients with daily doses less than 20 mg, significant differen ces in the C/D of haloperidol (P=0.003), but not of reduced haloperidol, we re found between the three major genotype groups. In patients with doses hi gher than 20 mg, no differences were found between the genotype groups for either haloperidol or reduced haloperidol. 68 patients (57%) used benztropi ne, an antimuscarinic agent. All four patients with a *5 allele (one togeth er with *1 and three with *10) were found to use benztropine. The patients homozygous for the *1 allele seemed to need less benztropine than the patie nts with one or two mutated alleles (Fisher's exact test; P=0.036). Conclusions The dose-corrected steady state plasma concentrations of halope ridol, but not of reduced haloperidol, were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when doses lower than 20 mg haloperidol were given. No differences were found at higher doses. Th ese results suggest the involvement of CYP2D6 in the metabolism of haloperi dol at low doses of haloperidol (< 20 mg daily), while another enzyme, prob ably CYP3A4, contributes at higher doses.