CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment.

BACKGROUND: The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites. METHODS: Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test. All statistical tests were two-sided. RESULTS: Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95% confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95% CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95%CI = 65.9 to 90.1 nM) (both P = .003). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95% CI = -86.1 to -19.5 nM, P = .0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites. CONCLUSION: Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.

Association between the CYP3A5 genotype and blood pressure.

We tested the hypothesis that the presence of a CYP3A5*1 allele is associated with increases in blood pressure in 2 studies of subjects with a total of 683 participants. The first study involving 271 subjects was part of a longitudinal study conducted at Indiana University Medical Center that consisted of 2 phases. The first phase studied the relationship of salt sensitivity with blood pressure, whereas the second phase, conducted approximately 26 years later, studied the relationship between blood pressure, carbohydrate intolerance, and vascular compliance in the same subjects. The second study was a cross-sectional evaluation of 412 normotensive and hypertensive subjects conducted at the University of California San Diego. The second study (Mantel-Haenszel chi(2) test; P=0.05) showed that a greater proportion of black participants with poor blood pressure control had CYP3A5*1/*1 genotype. Evaluation of the untreated blood pressure from phase 1 of the first study showed that the blacks with CYP3A5*3/*3 (146+/-35 mm Hg) had a higher systolic blood pressure than those with the *1/*3 (119+/-14.1 mm Hg; P=0.0006) and *1/*1 (125+/-17.4 mm Hg; P=0.009) genotypes. For blacks in study 2, the CYP3A5*1 allele was more common in hypertensives (Fisher exact test; P=0.025) than normotensives. In whites there was no association between CYP3A5 genotype and blood pressure in either study. We conclude that although untreated blood pressure may be higher in blacks with the CYP3A5*3/*3 genotype, the CYP3A5*1 allele may be associated with hypertension that is more refractory to treatment in this ethnic group.

Human sympathetic activation by alpha2-adrenergic blockade with yohimbine: Bimodal, epistatic influence of cytochrome P450-mediated drug metabolism.

BACKGROUND: alpha2-Adrenergic blockade responses suggest adrenergic dysfunction in hypertension. alpha2-Blockade is also used to treat autonomic dysfunction. However, pharmacokinetic determinants of yohimbine disposition are not understood. METHODS: We evaluated alpha2-blockade with intravenous yohimbine in 172 individuals. Specific cytochrome P450 (CYP) isoform-mediated metabolism was investigated. Results were evaluated by ANOVA and by maximum likelihood analysis for bimodality of response distributions. RESULTS: Yohimbine metabolism to 11-hydroxy-yohimbine displayed greater than 1000-fold variability, with 17 individuals showing no metabolism. Nonmetabolizers differed from others in ethnicity but not in age, sex, body habitus, blood pressure, heart rate, or family history of hypertension. Bimodality of metabolism was suggested by frequency histogram, as well as maximum likelihood and cluster analysis. Among ethnic groups, subjects of European ancestry had the highest frequency of nonmetabolism. In vitro oxidation suggested that the major route of metabolism (lowest Michaelis-Menten constant and greatest intrinsic clearance) was likely via CYP2D6 to 11-hydroxy-yohimbine. In vivo genotypes at both CYP2D6 and CYP3A4 were necessary to predict metabolism (overall F = 3.03, P =.005); an interaction of alleles at these 2 loci (interaction F = 3.05, P =.033) suggested an epistatic effect on drug metabolism in vivo. Nonmetabolizers had greater activation of sympathetic nervous system activity. Yohimbine increased blood pressure, an effect mediated hemodynamically by elevation of cardiac output rather than systemic vascular resistance. Blood pressure and cardiac output responses did not differ by metabolizer group. CONCLUSIONS: We conclude that heterogeneous, bimodally distributed yohimbine metabolism depends on common genetic variation in both CYP2D6 and CYP3A4 and contributes to differences in sympathetic neuronal response to alpha2-blockade. These results have implications for both diagnostic and therapeutic uses of this alpha2-antagonist.

Induction of testosterone metabolism by esomeprazole in a CYP2C19*2 heterozygote.

The authors describe a 42-year-old woman with previously normal sexual function who gradually developed loss of libido during treatment with esomeprazole. While taking esomeprazole, the patient's loss of libido improved with oral testosterone supplementation and deteriorated after testosterone withdrawal. There was steady improvement in both sexual function and serum free testosterone concentration after discontinuation of esomeprazole. Due to the temporal relationship between esomeprazole intake and sexual dysfunction, the authors postulate that esomeprazole causes induction of testosterone metabolism. The authors believe this to be the first case of female sexual dysfunction associated with esomeprazole described in the literature. They discuss a number of possible mechanisms for this effect.

Correlation between blood ethylenethiourea and thyroid gland disorders among banana plantation workers in the Philippines.

Ethylenebisdithiocarbamates (EBDCs) are metabolized into ethylenethiourea (ETU), a possible human carcinogen and an antithyroid compound. In this study our goal was to correlate ETU levels with the incidence of thyroid gland disorders among banana plantation workers exposed to EBDC. We randomly selected 57 directly exposed workers and 31 indirectly exposed workers from four banana plantations and 43 workers from an organic farm; all subjects underwent complete medical examinations and laboratory tests. Results showed a higher mean thyroid-stimulating hormone measurement among exposed workers compared with the control group, although the levels were well within normal range. Nine of the exposed farmers had abnormal thyroid ultrasound findings, consisting mostly of solitary nodules, compared with three among the control group. Analysis of variance showed significantly different blood ETU levels among the directly exposed, indirectly exposed, and control groups (p < 0.001), but ETU levels in urine were not significantly different (p = 0.10). Environmental ETU levels were below the U.S. Environmental Protection Agency remediation levels. Among farmers with solitary thyroid nodules, we found a very good direct correlation between the size of the nodule and blood ETU level. In this study we showed that blood ETU is a more reliable biomarker for EBDC exposure than urinary ETU; therefore, the determination of blood ETU should be part of medical surveillance efforts among workers exposed to EBDC to detect occurrences of thyroid gland disorders.