Pharmacogenetic aspects in the metabolism of psychotropic drugs: Pharmacokinetic and clinical implications

Cytochrome P450 (CYP) 2D6 activity is genetically determined, yielding extensive metabolizers (EMs) and poor metabolizers (PMs). Because of the involvement of this enzyme in the metabolism of many antipsychotic drugs, clinical implication of CYP2D6 genotyping has been expected for tailor-made antipsychotic drug therapy.

Genotyping analysis showed that the mean steady-state plasma concentration (C_ss) of haloperidol in subjects with no mutated alleles was higher than those in subjects with one and two mutated alleles. However, large overlaps in the C_ss were observed among these genotype groups. The C_ss of bromperidol was not affected by CYP2D6 genotypes. These results suggest that CYP2D6 genotype does not predict the C_ss of haloperidol or bromperidol. It was also shown that the active moiety of risperidone (plasma concentrations of risperidone plus 9-hydroxyrisperidone) did not differ between EMs and PMs of CYP2D6, although 9-hydroxylation of risperidone is highly dependent on CYP2D6 activity.

Nevertheless, CYP2D6 genotyping may be useful if drugs fulfill such conditions as: (1) specific substrates for CYP2D6, (2) established concentration–effect relationship, and (3) no active metabolites. High frequency of *10 allele in Orientals will also justify importance of CYP2D6 genotyping in subjects treated with such kind of antipsychotic drugs in the future.

The cytochrome P450 proteins (CYPs) are a family of haem proteins resulting from expression of a gene super-family that currently contains around 1000 members in species ranging from bacteria through to plants and animals. In humans, about 40 different CYPs are present and these play critical roles by catalyzing reactions in: (a) the metabolism of drugs, environmental pollutants and other xenobiotics; (b) the biosynthesis of steroid hormones; (c) the oxidation of unsaturated fatty acids to intracellular messengers; and (d) the stereo- and regio-specific metabolism of fat-soluble vitamins. This review deals with aspects of cytochrome P450s of relevance to human physiology, biochemistry, pharmacology and medicine. Topics reviewed include: pharmacogenetics of CYPs, induction and inhibition of these haem proteins, their role in metabolism of endogenous compounds such as steroids and eicosanoids, the effect of disease on CYP function, CYPs and cancer, and CYPs as targets of antibodies in immune-mediated diseases.

Expression of human cytochrome P450 (CYP) in heterologous cells is a means of specifically studying the role of these enzymes in drug metabolism. The complete cDNA encoding CYP2D6-VAL₃₇₄ was inserted into an expression vector containing the strong mycloproliferative sarcoma virus promotor in combination with the enhancer of the cytomegalovirus and stably expressed in V79 Chinese hamster cells. The presence of genomically integrated CYP2D6 cDNA was confirmed by polymerase chain reaction analysis. The protein expression was shown by Western blotting. Functional expression could be demonstrated by O-demethylation of dextromethorphan to dextrorphan in live cells. The enzymatic activity of 154 ± 16 pmol min⁻¹ mg⁻¹ protein was comparable with dextromethorphan-O-demethylation activities of human liver. The metabolism of two dopaminergic ergoline derivatives was investigated in whole recombinant V19 cells. Both lisuride and terguride were monodeethylated; in case of lisuride a correlation to the in vivo situation was demonstrated comparing poor and extensive metabolizers.

Metabolism of most drugs influences their pharmacological and toxicological effects. Drugs particularly affected are those with a narrow therapeutic window and that are subjected to considerable first-pass metabolism. Much of the interindividual and interethnic differences in effects of drugs is now attributable to genetic differences in their metabolism. Genetic polymorphisms have been described for many drug-metabolising enzymes in Caucasian and Oriental populations, the most well-characterised being those for cytochrome P450 2D6, cytochrome P450 2C19, glutathione S-transferases, and N-acetyl transferase 2. African populations have been studied to a lesser extent, but it is apparent that populations within Africa are heterogeneous with respect to these polymorphisms. In addition, although some allelic variants are common to all populations throughout the world (e.g., CYP2D6∗5), some allelic variants are specific for an African population (e.g., CYP2D6∗17). The polymorphisms give rise to enzymes with changed or no activity towards drug substrates. Two of the most important enzymes for metabolism of neuroleptics and other psychoactive drugs are CYP2D6 and CYP2C19. This article compares the current information on polymorphisms of these two enzymes in African and other populations and discusses the implications of these polymorphisms for neuropharmacotherapy.

This study examines the effects of genetically determined S-mephenytoin 4-hydroxylation capacity and cigarette smoking on the single-dose pharmacokinetics of oral alprazolam in 12 healthy male volunteers. Six subjects each were extensive metabolizers (EMs) and poor metabolizers (PMs) of S-mephenytoin 4-hydroxylation. Seven subjects were smokers (>10 cigarettes/day), and five were nonsmokers, according to their self-reports. Each subject took a single oral dose of 0.8 mg of alprazolam, and blood samples were collected up to 48 hours postdose. Psychomotor function was assessed at times of blood samplings using the Digit Symbol Substitution Test (DSST), Visual Analog Scale (VAS), and UKU Side Effect Rating Scale. Plasma alprazolam concentrations were measured by a high-performance liquid chromatography assay. None of the mean pharmacokinetic parameters was significantly different between the EM and PM phenotype groups. Although the mean elimination half-life was significantly shorter in the smoker group (p < .01) than in the nonsmokergroup (13.1 ± 2.9 vs. 20.0 ± 2.7 hours, mean ± SD), other pharmacokinetic parameters did not differ significantly between the two groups. Psychomotor function parameters did not differ significantly either between the EM and PM groups or between the nonsmoker and smoker groups. The present study thus suggests that neither S-mephenytoin 4-hydroxylation status nor self-reports of extensive cigarette smoking has a major impact on the metabolism of alprazolam in humans.