Previously, we demonstrated that the dose-normalized tacrolimus blood concentration after renal transplantation was associated with a single nucleotide polymorphism (SNP) in the CYP3AP1 gene, probably through linkage with an SNP in the CYP3A5 gene. Individuals with at least one CYP3A5*1 allele synthesize CYP3A5 and CYP3A5*3/*3 homozygotes do not. We now present results with direct typing of the CYP3A5 genotype for this group of 180 kidney-only transplant recipients from a single center. South Asian and white patients with at least one CYP3A5*1 allele achieved twofold lower dose-normalized tacrolimus blood concentrations compared with CYP3A5*3/*3 homozygotes, confirming our previous findings for the CYP3AP1 SNP. There was a significant delay in achieving target blood concentrations in those with at least one CYP3A5*1 allele. Determination of the CYP3A5*1/*3 genotype could be used to predict the tacrolimus dose requirement and, given incomplete linkage, would be better than determination of the CYP3AP1 genotype.

BackgroundSufficient levels of physical activity provide cardio-protective benefit. However within developed society sedentary work and inflexible working hours promotes physical inactivity. Consequently to ensure a healthy workforce there is a requirement for exercise strategies adaptable to occupational time constraint. This study examined the effect of a 12 week aerobic exercise training intervention programme implemented during working hours on the cardiovascular profile of a sedentary hospital workforce.MethodsTwenty healthy, sedentary full-time staff members of the North West London Hospital Trust cytology unit were randomly assigned to an exercise (n = 12; mean ± SD age 41 ± 8 years, body mass 69 ± 12 kg) or control (n = 8; mean ± SD age 42 ± 8 years, body mass 69 ± 12 kg) group. The exercise group was prescribed a progressive aerobic exercise-training programme to be performed 4 times a week for 8 weeks (initial intensity 65% peak oxygen consumption (VO2 peak)) and to be conducted without further advice for another 4 weeks. The control was instructed to maintain their current physical activity level. Oxygen economy at 2 minutes (2minVO2), 4 minutes (4minVO2), VO2 peak, systolic blood pressure (SBP), diastolic blood pressure (DBP), BMI, C-reactive protein (CRP), fasting glucose (GLU) and total cholesterol (TC) were determined in both groups pre-intervention and at 4 week intervals. Both groups completed a weekly Leisure Time Questionnaire to quantify additional exercise load.ResultsThe exercise group demonstrated an increase from baseline for VO2 peak at week 4 (5.8 ± 6.3 %) and 8 (5.0 ± 8.7 %) (P < 0.05). 2minVO2 was reduced from baseline at week 4 (-10.2 ± 10.3 %), 8 (-16.8 ± 10.6 %) and 12 (-15.1 ± 8.7 %), and 4minVO2 at week 8 (-10.7 ± 7.9 %) and 12 (-6.8 ± 9.2) (P < 0.05). There was also a reduction from baseline in CRP at week 4 (-0.4 ± 0.6 mg·L-1) and 8 (-0.9 ± 0.8 mg·L-1) (P < 0.05). The control group showed no such improvements.ConclusionThis is the first objectively monitored RCT to show that moderate exercise can be successfully incorporated into working hours, to significantly improve physical capacity and cardiovascular health.

P-glycoprotein (P-gp) and the drug metabolizing enzymes have major pharmacokinetic effects. Variability in tacrolimus absorption is influenced by P-gp activity which, in turn, is affected by single nucleotide polymorphisms (SNPs) within the multidrug resistance-1 gene (MDR-1). Tacrolimus dose requirements of 206 stable renal transplant patients were related to MDR-1 genotypes of SNPs C1236T, G2677T/A and C3435T, as well as haplotypes: C-G-C and T-T-T. Lower dose-normalized blood tacrolimus concentrations were achieved for: 2677-GG genotype patients, as compared to 2677-TT, and for 3435-CC patients as compared to 3435-TT patients. There was a small, but significant, difference in dose requirements between haplotypes C-G-C and T-T-T patients, which was not significant when patients were subclassified as producers and non-producers of cytochrome P450 3A5 (CYP3A5). The activities of CYP3A5 and P-gp have been shown to influence bioavailability of several drugs. Our data suggest that MDR-1 haplotypes have a relatively minor association with tacrolimus pharmacokinetics.

Among Zimbabweans, LoF haplotypes constitute the majority of CYP2B6 alleles and are significantly higher in prevalence compared with Ugandans. Frequencies of LoF haplotypes and SNPs in Ugandan Nilotics appear to lie between those of Zimbabweans and Ugandan Bantus. These findings may have relevance to pharmacokinetics and dosing of efavirenz in African populations.

The intestinal efflux pump P-glycoprotein (P-gp), the product of the multi-drug resistance-1 (MDR-1) gene, significantly influences the pharmacokinetics of several drugs. Ciclosporin is a substrate for P-gp and is metabolized by cytochrome P450 (CYP) 3A enzymes. P-gp activity is affected by several known single nucleotide polymorphisms (SNPs) and haplotypes. MDR-1 genotypes of SNPs C1236T, G2677T/A and C3435T, as well as haplotypes C-G-C and T-T-T and CYP3A5*1 genotype (predictive of CYP3A5 expression), were related to ciclosporin blood concentrations measured at both 0 and 2 h after drug dosing in 197 stable renal transplant patients. Significant differences (of a magnitude unlikely to be relevant clinically) in dose-normalized blood ciclosporin concentrations were found only between MDR-1 genotypes of the C1236T SNP and between haplotype groups C-G-C and T-T-T in patients that were expressers of CYP3A5. MDR-1 SNPs and haplotypes and also CYP3A5*1 genotype, do not appear to have a major influence on ciclosporin pharmacokinetics.