Frequency of cytochrome P-450 3A4 variant genotype in transplant population and lack of association with cyclosporin clearance

Objective: Cytochrome P-450 3A4 (CYP3A4) plays a vital role in the oxidativ e metabolism of many xenobiotics. Some recent reports have provided circums tantial evidence in support of an association between a genetic polymorphis m (A-->G) in the 5'-flanking region (-290) of CYP3A4 and altered enzyme act ivity. We sought to determine whether genotyping patients for CYP3A4-G coul d assist with the dose optimisation of drugs metabolised by this system. Methods: Normal subjects and renal-transplant patients receiving cyclospori n for immune modulation were genotyped for the CYP3A4-G variant. A surrogat e for cyclosporin clearance was estimated from the ratio of the cyclosporin dose, normalised for body weight and the corresponding trough concentratio n. The association between genotype and clearance was examined in patients who received twice-daily doses of cyclosporin and who were not on concurren t medication known to modify CYP3A4 function. Results: The allelic frequencies of the CYP3A4-G variant were estimated to be 2.6% and 3% in transplant patients and normal subjects, respectively. Th e median cyclosporin pseudo-clearance of transplant patients with wild-type CYP3A4 was 0.90 l/h/kg (range: 0.35-3.8 l/h/ kg; n = 86), whereas the corr esponding value for the five patients heterozygotic for the CYP3A4-G varian t was 0.71 l/h/kg (range 0.35-0.91 l/h/kg). The distribution of the pseudo- clearance according to genotype was not found to be significant according t o a Fisher's exact test (P = 0.15). Conclusion: Genotyping for the CYP3A4-G polymorphism is unlikely to assist cyclosporin dose selection in transplant patients.