The cytochrome P450 3A (CYP3A) subfamily members are the most abundant and important drug-metabolizing enzymes in humans, and wide interindividual variability in CYP3A expression and function is present. CYP3A4 alone cannot fully explain the observed constitutive variability because its genetic variants are relatively uncommon and have limited functional significance, whereas CYP3A5 expression in humans is highly variable and may be contributory. However, it is difficult to delineate the relative contribution of CYP3A4 and CYP3A5, and to differentiate their effects on drug metabolism as their protein structure, function and substrates are so similar. By contrast, molecular biology methods provide the ability to identify CYP3A4 and CYP3A5 genotypes with certainty. This review collates currently available data on CYP3A5 polymorphisms, provides information on the population frequency of each genetic variant in major ethnic groups, and describes in vitro and in vivo studies that have attempted to identify genotype-phenotype associations.

Recent epidemiologic studies have suggested that genetic polymorphisms in the cytochrome P-450 1A1 gene (CYP1A1) may affect the relation between environmental exposure to polychlorinated biphenyls (PCBs) and breast cancer risk. The authors report results from a case-control study evaluating the potential effect of gene-environment interaction between CYP1A1 and serum PCB levels on breast cancer risk among Caucasian women in Connecticut. The study included 374 case women with histologically confirmed breast cancer and 406 noncancerous controls with information on both serum PCB level and CYP1A1 genotype (1999-2002). Compared with women who had the homozygous wild-type CYP1A1 m2 genotype, significantly increased risks of breast cancer were found for women with the CYP1A1 m2 variant genotype (odds ratio (OR) = 2.1, 95% confidence interval (CI): 1.1, 3.9), especially postmenopausal women (OR = 2.4, 95% CI: 1.1, 5.0). Risks associated with the CYP1A1 m2 variant genotype were highest for all women (OR = 3.6, 95% CI: 1.5, 8.2) and postmenopausal women (OR = 4.3, 95% CI: 1.6, 12.0) with higher serum PCB levels (611-2,600 ng/g). The CYP1A1 m1 and m4 genotypes were not associated with breast cancer risk independently or in combination with PCB exposure. In summary, the CYP1A1 m2 genetic polymorphism was associated with increased risk of female breast cancer and may modify the relation between PCB exposure and breast cancer risk.

The population pharmacokinetic (PK) profile of oral clonidine was characterized in newborns with neonatal abstinence syndrome, and significant covariates affecting its PK parameters were identified. Plasma clonidine concentration data were obtained from a clinical trial in which 36 newborns, aged 1 to 25 days (postnatal age, PNA) and weighing 2.1 to 3.9 kg, were enrolled to take multiple oral doses of clonidine. The population PK model of clonidine was developed by NONMEM, and significant covariates were identified, followed by nonparametric bootstraps (2000 replicates) and simulation experiments. A 1-compartment open linear PK model was chosen to describe plasma concentrations of clonidine, and body weight and PNA were significant covariates for apparent clearance (CL/F) as follows: CL/F (L/h) = 15.2 × [body weight (kg)/70](0.75) × [PNA (day)(0.441)/(4.06(0.441) + PNA (day)(0.441))]. Furthermore, CL/F of clonidine increased rapidly with PNA during the first month of life after body weight was adjusted. Any optimal dosage regimen for clonidine in term neonates should be based on infant's age and body weight, and 1.5 µg/kg every 4 hours is proposed starting the second week of life based on the simulation results.

These data suggest that although there are marked ethnic differences in their distribution, the common genetic polymorphisms of the human beta2-adrenergic receptor gene do not cosegregate with the presence of hypertension in either black or white Americans.