Nicotine metabolism and CYP2A6 allele frequencies in Koreans.

CYP2A6 is a major catalyst of nicotine metabolism to cotinine. Previously, we demonstrated that the interindividual difference in nicotine metabolism is related to a genetic polymorphism of the CYP2A6 gene in Japanese. To clarify the ethnic differences in nicotine metabolism and frequencies of CYP2A6 alleles, we studied nicotine metabolism and the CYP2A6 genotype in 209 Koreans. The cotinine/nicotine ratio of the plasma concentration 2 h after chewing one piece of nicotine gum was calculated as an index of nicotine metabolism. The genotypes of CYP2A6 gene (CYP2A6*1A, CYP2A6*1B, CYP2A6*2, CYP2A6*3, CYP2A6*4 and CYP2A6*5) were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism or allele specific (AS)-PCR. There were ethnic differences in the allele frequencies of CYP2A6*1A, CYP2A6*1B, CYP2A6*4 and CYP2A6*5 between Koreans (45.7%, 42.8%, 11.0% and 0.5%, respectively) and Japanese (42.4%, 37.5%, 20.1% and 0%, respectively, our previous data). Similar to the Japanese, no CYP2A6*2 and CYP2A6*3 alleles were found in Koreans. The homozygotes of the CYP2A6*4 allele (four subjects) were completely deficient in cotinine formation, being consistent with the data among Japanese. The heterozygotes of CYP2A6*4 tended to possess a lower metabolic ratio (CYP2A6*1A/CYP2A6*4, 4.79 +/- 3.17; CYP2A6*1B/CYP2A6*4, 7.43 +/- 4.97) than that in subjects without the allele (CYP2A6*1A/CYP2A6*1A, 7.42 +/- 6.56; CYP2A6*1A/CYP2A6*1B, 9.85 +/- 16.12; CYP2A6*1B/CYP2A6*1B, 11.33 +/- 9.33). The subjects who possess the CYP2A6*1B allele appeared to show higher capabilities of cotinine formation. It was confirmed that the interindividual difference in nicotine metabolism was closely related to the genetic polymorphism of CYP2A6. The probit plot of the metabolic ratios in Koreans (8.73 +/- 11.88) was shifted to a higher ratio than that in the Japanese (3.78 +/- 3.09). In each genotype group, the Korean subjects revealed significantly higher metabolic ratios than the Japanese subjects. The ethnic difference in cotinine formation might be due to environmental and/or diet factors as well as genetic factors.     

Nicotine metabolism and CYP2A6 activity in a population of black African descent: impact of gender and light smoking

Genetic variation in CYP2A6 (the main nicotine metabolizing enzyme) accounts for some, but not all, of the interindividual and interethnic variability in the rates of nicotine metabolism. We conducted a nicotine kinetic study in smokers and nonsmokers of black African descent (N=190), excluding those with common genetic variants in CYP2A6, to investigate the association of demographic variables with CYP2A6 activity (3HC/COT ratio) and nicotine disposition kinetics (estimated nicotine AUC). An additional aim was to examine whether impaired CYP2A6 activity and/or nicotine disposition kinetics were associated with lower cigarette consumption in a population of light smokers (mean相似文献   

Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity

STUDY OBJECTIVE: To evaluate the metabolism of antipyrine, a general metabolic probe, caffeine, a probe for cytochrome P450 (CYP) 1A2 and N-acetyltransferase activity, and dextromethorphan, a specific probe for CYP2D6 activity in patients with type 1 or 2 diabetes mellitus. DESIGN: Prospective, controlled study. SETTING: Research facility. Patients. Fifteen patients with type 1 and 16 with type 2 diabetes, and 16 healthy controls. INTERVENTION: Each subject simultaneously received antipyrine 10 mg/kg, caffeine 100 mg, and dextromethorphan 30 mg. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of antipyrine and its primary metabolites were determined from saliva and urine samples. Type 1 diabetes had marked effects on antipyrine metabolism whereas type 2 disease did not alter the metabolism of any of the probe drugs. The apparent oral clearance of antipyrine was increased 72% in patients with type 1 disease compared with controls (p=0.0001). In addition, formation clearances of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine were increased by 74% and 137% in those patients relative to controls. The caffeine metabolic index (paraxanthine/caffeine) was increased 34% (p=0.11), and N-acetylation and CYP2D6 phenotype were not altered. CONCLUSION: The metabolism of antipyrine is increased in patients with type 1 diabetes. Based on in vitro reports of antipyrine metabolism and current caffeine metabolic index data, the predominant effect of type 1 diabetes appears to be an increase in CYP1A2 activity. Assessment of the effect of the disease on other specific CYP metabolic pathways is warranted.     

Hepatic CYP2A6 levels and nicotine metabolism: impact of genetic, physiological, environmental, and epigenetic factors

Purpose  

We investigated the role of genetic, physiological, environmental, and epigenetic factors in regulating CYP2A6 expression and nicotine metabolism.     

CYP2A13-catalysed coumarin metabolism: comparison with CYP2A5 and CYP2A6

1. We investigated the total metabolism of coumarin by baculovirus (BV)-expressed CYP2A13 and compared it with metabolism by BV-expressed CYP2A6. The major coumarin metabolite formed by CYP2A13 was 7-hydroxycoumarin, which accounted for 43% of the total metabolism. The product of 3,4-epoxidation, o-hydroxyphenylacetaldehyde (o-HPA), accounted for 30% of the total metabolites. 2. The K(m) and V(max) for CYP2A13-mediated coumarin 7-hydroxylation were 0.48+/-0.07 micro m and 0.15+/-0.006 nmol min(-1) nmol(-1) CYP, respectively. The V(max) of coumarin 7-hydroxylation by CYP2A13 was about 16-fold lower than that of CYP2A6, whereas the K(m) was 10-fold lower. 3. In the mouse, there were two orthologues for CYP2A6: CYP2A4 and CYP2A5, which differed by only 11 amino acids. However, CYP2A5 is an efficient coumarin 7-hydroxylase, where as CYP2A4 is not. We report here that BV-expressed CYP2A4 metabolizes coumarin by 3,4-epoxidation. Two products of the 3,4-epoxidation pathway, o-HPA and o-hydroxyphenylacetic acid (o-HPAA), were detected by radioflow HPLC. 4. The K(m) and V(max) for the coumarin 3,4-epoxidation by CYP2A4 were 8.7+/-3.6 micro m and 0.20+/-0.04 nmol min(-1) nmol(-1) CYP, respectively. Coumarin 7-hydroxylation by CYP2A5 was more than 200 times more efficient than 3,4 epoxidation by CYP2A4.     

Interindividual differences in nicotine metabolism and genetic polymorphisms of human CYP2A6

Nicotine is widely consumed throughout the world, and exerts a number of physiological effects. After nicotine is absorbed through the lungs by cigarette smoking, it undergoes extensive metabolism in humans. Nicotine is mainly metabolized to cotinine by cytochrome P450 (CYP) 2A6. CYP2A6 can metabolize some pharmaceutical agents such as halothane, valproic acid, and fadrozole, and activate tobacco-specific nitrosamines. There are large interindividual differences in nicotine metabolism, and it has been found that the interindividual differences are attributed to the genetic polymorphisms of CYP2A6 gene. This review describes the techniques for determination of in vivo nicotine metabolism, characteristics of each human CYP2A6 alleles, and ethnic differences. The relationship between CYP2A6 genetic polymorphism and potency of nicotine metabolism, smoking behavior, and cancer risk are extensively reviewed. Finally, the usefulness of nicotine metabolism for phenotyping of CYP2A6 in individuals and implication of the significance of CYP2A6 genetic polymorphism in a clinical perspective are discussed.     

CYP2D6基因多态性及对美托洛尔代谢的影响

CYP2D6是一种重要的P450系氧化代谢酶,主要参与多种重要药物的代谢。CYP2D6基因多态性会引起药物代谢有显著的个体和种族差异。美托洛尔为选择性β1受体阻滞剂,临床应用上存在巨大个体差异,主要在肝脏经多条途径代谢,大约70%的代谢由CYP2D6介导,CPY2D6基因多态性对美托洛尔代谢有较大影响。本文从CYP2D6的基因多态性及它对美托洛尔代谢的影响这两方面作一综述。     

CYP2D6基因多态性及对药物代谢的影响

CYP2D6代谢酶是细胞色素P450家族中的成员之一,是参与Ⅰ相代谢和众多内源性物质和不同药物消除的酶。虽然它在肝脏中的含量大约只占肝脏总量的2%,但在临床上却参与了25%以上的常用药物的代谢活动。在所有参与药物代谢的细胞色素P450基因家族中,CYP2D6是唯一不能被诱导的酶,这种酶具有广泛的多态性,这种多态性对酶的药物代谢功能具有重要影响,CYP2D6的这种多态性和药物代谢功能所表现的对个体活性的差异,在遗传药理学上具有重要意义。本文从CYP2D6基因多态性和它对药物代谢的影响这两方面进行了阐述。     

The influence of CYP2A6 polymorphisms and cadmium on nicotine metabolism in Thai population

We investigated the influence of genetic, cadmium exposure and smoking status, on cytochrome P450-mediated nicotine metabolism (CYP2A6) in 182 Thai subjects after receiving 2 mg of nicotine gum chewing for 30 min. The urinary excretion of cotinine was normally distributed over a 2 h period (logarithmically transformed). Individuals with urinary cotinine levels in the ranges of 0.01–0.21, and 0.52–94.99 μg/2 h were categorized as poor metabolizes (PMs: 6.5%), and extensive metabolizers (EMs: 93.5%), respectively. The majority of EMs (45%) carried homozygous wild-type genotypes (CYP2A6*1A/*1A, CYP2A6*1A/*1B and CYP2A6*1B/*1B), whereas only 1% of PMs carried these genotypes. Markedly higher frequencies of EMs were also observed in all heterozygous defective genotypes including the null genotype (*4C/*4C; 1 subject).A weak but significant positive correlation was observed between total amounts of urinary cadmium excretion and total cotinine excretion over 2 h. Our study shows generally good agreement between CYP2A6 genotypes and phenotypes. Smokers accumulated about 3–4-fold higher mean total amounts of 2-h urinary cadmium excretion (127.5 ± 218.2 ng/2 h) than that of non-smokers (40.5 ± 78.4 ng/2 h). Among the smokers (n = 16), homologous wild-type genotype *1/*1 was significantly the predominant genotype (6/16) compared with other defective allele including *4C/*4C. In addition, 2 h urinary excretion of cotinine in smokers of all genotypes was significantly higher than non-smokers. The proportion of smokers who smoked more than 5 cigarettes/day was significantly higher in EMs in all CYP2A6 genotypes (n = 14) than in PMs (n = 0).     

Gene-gene interactions between CYP2B6 and CYP2A6 in nicotine metabolism

OBJECTIVES: CYP2A6 is the major enzyme involved in nicotine metabolism, yet large interindividual variations in the rate of nicotine metabolism exist within groups of individuals having the same CYP2A6 genotype. We investigated the influence of genetic variation in another potential nicotine-metabolizing enzyme, CYP2B6, and its interaction with CYP2A6, on the metabolism of nicotine. METHODS: Two hundred and twelve healthy Caucasian adult twin volunteers underwent an intravenous infusion of stable isotope-labeled nicotine and its major metabolite, cotinine, for characterization of pharmacokinetic and metabolism phenotypes. Five CYP2B6 genetic polymorphisms causing amino acid substitutions (R22C, Q172 H, S259R, K262R, and R487C) were analyzed. RESULTS: We observed that the CYP2B6*6 haplotype (defined as having both Q172 H and K262R variants) was associated with faster nicotine and cotinine clearance, and that such associations were more prominent among individuals having decreased-activity CYP2A6 genotypes. Statistically significant interactions between CYP2B6 and CYP2A6 genotypes were observed (P<0.003 for nicotine clearance and P<0.002 for cotinine clearance). CONCLUSIONS: Our results indicate that CYP2B6 genetic variation is associated with the metabolism of nicotine and cotinine among individuals with decreased CYP2A6 activity. Further investigation of the roles of CYP2B6 and the interaction between CYP2B6 and CYP2A6 genotypes in mediating nicotine dependence and tobacco-related diseases is merited.     

The influence of CYP2A6 polymorphisms and cadmium on nicotine metabolism in Thai population

We investigated the influence of genetic, cadmium exposure and smoking status, on cytochrome P450-mediated nicotine metabolism (CYP2A6) in 182 Thai subjects after receiving 2 mg of nicotine gum chewing for 30 min. The urinary excretion of cotinine was normally distributed over a 2 h period (logarithmically transformed). Individuals with urinary cotinine levels in the ranges of 0.01–0.21, and 0.52–94.99 μg/2 h were categorized as poor metabolizes (PMs: 6.5%), and extensive metabolizers (EMs: 93.5%), respectively. The majority of EMs (45%) carried homozygous wild-type genotypes (CYP2A6*1A/*1A, CYP2A6*1A/*1B and CYP2A6*1B/*1B), whereas only 1% of PMs carried these genotypes. Markedly higher frequencies of EMs were also observed in all heterozygous defective genotypes including the null genotype (*4C/*4C; 1 subject).A weak but significant positive correlation was observed between total amounts of urinary cadmium excretion and total cotinine excretion over 2 h. Our study shows generally good agreement between CYP2A6 genotypes and phenotypes. Smokers accumulated about 3–4-fold higher mean total amounts of 2-h urinary cadmium excretion (127.5 ± 218.2 ng/2 h) than that of non-smokers (40.5 ± 78.4 ng/2 h). Among the smokers (n = 16), homologous wild-type genotype *1/*1 was significantly the predominant genotype (6/16) compared with other defective allele including *4C/*4C. In addition, 2 h urinary excretion of cotinine in smokers of all genotypes was significantly higher than non-smokers. The proportion of smokers who smoked more than 5 cigarettes/day was significantly higher in EMs in all CYP2A6 genotypes (n = 14) than in PMs (n = 0).     

Effects of CYP2D6 genotypes on age-related change of flecainide metabolism: involvement of CYP1A2-mediated metabolism

AIMS

The aim of this study was to clarify the effects of CYP2D6 genotype on age-related change in flecainide metabolism in patients with supraventricular tachyarrhythmias. An in vitro study using microsomes was performed to identify other CYPs responsible for age-related change in flecainide metabolism.

METHODS

The study population comprised 111 genotyped patients: CYP2D6-homozygous extensive metabolizers (hom-EMs, n= 34), heterozygous EMs (het-EMs, n= 56), and intermediate and poor metabolizers (IMs/PMs, n= 21). Serum concentrations of flecainide and its metabolites [m-O-dealkylated flecainide (MODF) and m-O-dealkylated lactam of flecainide] were determined by use of a high-performance liquid chromatography. Metabolic ratio (MR) was expressed as serum concentrations of flecainide to its metabolites. In vitro formation of MODF was examined in human liver microsomes and cDNA-expressed CYP isoforms.

RESULTS

MR was higher in elderly patients (≥70 years) than in middle-aged patients (<70 years). The increase of MR in elderly patients differed among CYP2D6 genotypes: 1.6-fold in het-EMs [4.3, 95% confidence interval (CI) 2.8, 5.7 vs. 2.7, 95% CI 2.3, 3.1, P < 0.05], 1.5-fold in IMs/PMs (6.0, 95% CI 4.5, 7.6 vs. 4.1, 95% CI 2.9, 5.4, P < 0.05), and no change in hom-EMs. The in vitro study using microsomes revealed that both CYP2D6 and CYP1A2 were involved in the formation of MODF. MODF formation in CYP2D6 PM microsomes increased as CYP1A2 activity increased.

CONCLUSIONS

The results suggest that patients with poor CYP2D6-mediated metabolism (het-EMs and IMs/PMs) showed age-related reduction in flecainide metabolism because metabolism was taken over by CYP1A2, whose activity decreases with age.     

CYP2A6 genetic variation and dexmedetomidine disposition

Purpose

There is a large interindividual variability in dexmedetomidine dose requirements for sedation of patients in intensive care units (ICU). Cytochrome P450 2A6 (CYP2A6) mediates an important route of dexmedetomidine metabolism, and genetic variation in CYP2A6 affects the clearance of other substrate drugs. We examined whether CYP2A6 genotypes affect dexmedetomidine disposition.

Methods

In 43 critically ill ICU patients receiving dexmedetomidine infusions adjusted to achieve the desired level of sedation, we determined a median of five plasma dexmedetomidine concentrations each. Forty subjects were genotyped for five common CYP2A6 alleles and grouped into normal (n?=?33), intermediate (n?=?5), and slow metabolizers (n?=?2).

Results

Using a Bayesian hierarchical nonlinear mixture model, estimated dexmedetomidine clearance was 49.1?L/h (posterior mean; 95% credible interval 41.4–57.6?L/h). There were no significant differences in dexmedetomidine clearance among normal, intermediate, and slow CYP2A6 metabolizer groups.

Conclusion

Genetic variation in CYP2A6 does not appear to be an important determinant of dexmedetomidine clearance in ICU patients.     

The impact of CYP2C19 and CYP2D6 genotypes on metabolism of amitriptyline in Japanese psychiatric patients

We investigated the effect of the CYP2C19 and CYP2D6 genotypes on the metabolism of amitriptyline (AT) in Japanese psychiatric patients. Steady-state concentrations of AT and its metabolites (nortriptyline [NT], trans-10-hydroxy-nortriptyline [EHNT], cis-10-hydroxy-nortriptyline [ZHNT], trans-10-hydroxy-amitriptyline [EHAT], and cis-10-hydroxy-amitriptyline [ZHAT]) in 50 patients were determined by high-performance liquid chromatography. Significantly higher plasma concentrations of AT corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 were observed (no mutated alleles vs. two mutated alleles: 36.0 +/- 18.2 vs. 64.0 +/- 25.2 ng/mL/mg/kg, p = 0.025). A significantly higher AT/NT ratio was seen in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 (no mutated alleles vs. two mutated alleles: 1.27 +/- 0.59 vs. 3.40 +/- 1.02, p = 0.001). A trend for higher NT/EHNT ratio in the subjects with two mutated alleles of CYP2D6 than in those with no mutated alleles of CYP2D6 was observed (no mutated alleles vs. two mutated alleles: 0.73 +/- 0.39 vs. 1.31 +/- 0.81, p = 0.068). A trend for higher plasma concentrations of total hydroxylated metabolites of AT (EHAT + ZHAT) corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 was found (no mutated alleles vs. two mutated alleles: 9.5 +/- 5.8 vs. 17.8 +/- 8.9, p = 0.051). Therefore, the genotype of CYP2C19 is one of the important determinants of the plasma concentrations of AT and the capacity to desmethylate AT. Mother compound AT is shunted via hydroxylation pathways from AT to EHAT and ZHAT in the subjects with homozygotes of mutated alleles of CYP2C19 in order to compensate for the decreased capacity to desmethylate AT.     

Effect of CYP2B6*6 and CYP2C19*2 genotype on chlorpyrifos metabolism

Chlorpyrifos (CPF) is a widely used organophosphorus (OP) pesticide. CPF is bioactivated by cytochrome P450s (CYPs) to the potent cholinesterase inhibitor chlorpyrifos oxon (CPF-O) or detoxified to 3,5,6-trichloro-2-pyridinol (TCPy). Human CYP2B6 has the highest reported Vmax)/Km (intrinsic clearance--CL(int)) for bioactivation while CYP2C19 has the highest reported CL(int) for detoxification of CPF. In this study, 22 human liver microsomes (HLMs) genotyped for common variants of these enzymes (CYP2B6*6 and CYP2C19*2) were incubated with 10 μM and 0.5 μM CPF and assayed for metabolite production. While no differences in metabolite production were observed in homozygous CYP2C19*2 HLMs, homozygous CYP2B6*6 specimens produced significantly less CPF-O than wild-type specimens at 10 μM (mean 144 and 446 pmol/min/mg, respectively). This correlated with reduced expression of CYP2B6 protein (mean 4.86 and 30.1 pmol/mg, for CYP2B6*6 and *1, respectively). Additionally, CYP2B6*1 and CYP2B6*6 were over-expressed in mammalian COS-1 cells to assess for the first time the impact of the CYP2B6*6 variant on the kinetic parameters of CPF bioactivation. The Vmax for CYP2B6*6 (1.05×10? pmol/min/nmol CYP2B6) was significantly higher than that of CYP2B6*1 (4.13×10? pmol/min/nmol CYP2B6) but the K(m) values did not differ (1.97 μM for CYP2B6*6 and 1.84 μM for CYP2B6*1) resulting in CL(int) rates of 53.5 and 22.5 nL/min/nmol CYP2B6 for *6 and *1, respectively. These data suggest that CYP2B6*6 has increased specific activity but reduced capacity to bioactivate CPF in HLMs compared to wild-type due to reduced hepatic protein expression, indicating that individuals with this genotype may be less susceptible to CPF toxicity.     

CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response

Paroxetine is characterized by large interindividual pharmacokinetic variability and heterogeneous response patterns. The present study investigates plasma concentration and therapeutic response to paroxetine for the influence of age, sex, and CYP2D6 and ABCB1 polymorphisms, the latter gene encoding for the permeability glycoprotein. Genotyping for CYP2D6 (alleles *3, *4, *5, *6, and *xN) and ABCB1 polymorphisms (61A>G, 2677G>T, and 3435C>T) was performed in 71 depressed patients who started 20 mg paroxetine per day and had plasma concentration measured after 2 weeks at a fixed dose. A dose increase to 30 mg per day was possible starting at week 2. For 63 patients, severity of depression (Montgomery-Asberg Depression Rating Scale) was assessed at weeks 0, 2, and 4 and every 2 weeks thereafter until discontinuation. Persistent response was defined as 50% improvement from baseline score sustained from the first occurrence to study end point. Paroxetine concentration significantly differed between female and male patients (median, 28 versus 16 ng/mL; P = 0.001). Differences were not significant between CYP2D6 heterozygous and homozygous extensive metabolizers (median, 27 versus 22 ng/mL; P = 0.074) and between ABCB1 genotypes (P > 0.10). When considered in a multivariate model, CYP2D6 heterozygous extensive metabolizer phenotype (P = 0.062) and female gender (P = 0.001) predicted 1.3-fold and 1.6-fold higher paroxetine concentration, respectively, but fraction of explained variability was modest (21%). Frequency of persistent response at study end point did not significantly differ according to CYP2D6 heterozygous extensive metabolizer versus homozygous extensive metabolizer phenotype and ABCB1 polymorphisms in univariate analyses. After adjusting for age, sex, paroxetine concentration at week 2, and daily dose at study end point, ABCB1 genotype contributed to improving the model significantly for 61A>G (P = 0.043), but not 2677G>T (P = 0.068) and 3435C>T (P = 0.11). None of two poor metabolizers and four ultrarapid metabolizers showed persistent response to paroxetine. The hypothesis that permeability glycoprotein activity might be a relevant predictor of therapeutic response deserves to be further investigated while controlling for pharmacokinetic variability.     

Prolactin release in children treated with risperidone: impact and role of CYP2D6 metabolism

OBJECTIVE: Little is known about the role of CYP2D6 polymorphism in risperidone-induced prolactin release in children. METHOD: Twenty-five children (aged 5-15 years) with pervasive developmental disorders were genotyped for CYP2D6 polymorphisms. Serum prolactin, risperidone, and 9-hydroxyrisperidone were assessed at baseline and after 8 weeks of risperidone treatment (mean dosage, 0.06 +/- 0.03 mg/kg/d). After 24 weeks of treatment, prolactin was measured in a subsample of 15 children. Adverse effects were evaluated using a clinician-rated survey. RESULTS: Mean +/- SD prolactin levels increased from 7.8 +/- 8.0 ng/mL at baseline to 33.2 +/- 12.8 ng/mL at week 8 (P < 0.001), with a slight decrease to 28.8 +/- 13.6 ng/mL at week 24. At week 8, serum prolactin level was positively correlated with dose per kilogram (r = 0.648, P < 0.001), number of functional CYP2D6 genes (J = 2.117, P = 0.034), and serum 9-hydroxyrisperidone concentration (r = 0.664, P = 0.001) and was negatively correlated with the risperidone/9-hydroxyrisperidone ratio (r = -0.571, P = 0.004) but not with risperidone concentration (r = -0.243, P = 0.264) nor age (r = 0.072, P = 0.733). Prolactin elevation was not associated with adverse effects. CONCLUSIONS: Low-to-intermediate doses of risperidone induced a 4-fold prolactin increase in children without a clear development of tolerance up to 6 months. CYP2D6 ultrarapid metabolism may be a risk factor for more pronounced prolactin elevation.     

Stereoselectivity in metabolism of ifosfamide by CYP3A4 and CYP2B6

The aim was to identify the hepatic cytochromes P450 (CYPs) responsible for the enantioselective metabolism of ifosfamide (IFA). The 4-hydroxylation, N²- and N³-dechloroethylation of IFA enantiomers were monitored simultaneously in the same metabolic systems using GC/MS and pseudoracemate techniques. In human and rat liver microsomes, (R)-IFA was preferentially metabolized via 4-hydroxylation, whereas its antipode was biotransformed in favour of N-dechloroethylation. CYP3A4 was the major enzyme responsible for metabolism of IFA enantiomers in human liver. The study also revealed that CYP3A (human CYP3A4/5 and rat CYP3A1/2) and CYP2B (human CYP2B6 and rat CYP2B1/2) enantioselectively mediated the 4-hydroxylation, N²- and N³-dechloroethylation of IFA. CYP3A preferentially supported the formation of (R)-4-hydroxyIFA (HOIF), (R)-N²-dechloroethylIFA (N2D) and (R)-N³-dechloroethylIFA (N3D), whereas CYP2B preferentially mediated the generation of (S)-HOIF, (S)-N2D and (S)-N3D. The enantioselective metabolism of IFA by CYP3A4 and CYP2B1 was confirmed in cDNA transfected V79 cells.