CYP3A5*1/*3 genotype influences the blood concentration of tacrolimus in response to metabolic inhibition by ketoconazole.
OBJECTIVE
Ketoconazole retards metabolic degradation of tacrolimus through its effect on the cytochrome P-450 enzyme system and allows reduction in treatment costs. Enzyme activity is determined by a single nucleotide polymorphism (*1/*3) in the CYP3A5 gene.


METHODS
We prospectively investigated the impact of this polymorphism on tacrolimus concentration in a cohort of 79 renal transplant recipients on ketoconazole. Genotyping was carried out by using polymerase chain reaction-restriction fragment length polymorphism technique. Dose-adjusted trough level (C0) was calculated at baseline and at 3, 7, 15, 30, and 60 days.


RESULTS
The baseline C0 was significantly lower in those with at least one *1 allele [44.95+/-14.12 vs. 63.43+/-14.72 (ng/ml)/(mg/kg/day), P<0.0001]. After starting ketoconazole in all genotypes, dose-normalized C0 increased and the cost of therapy decreased. Compared with baseline, the magnitude of increase was 112% and 79% in those without and with *1 allele, respectively (P<0.001). The cost savings were 32% and 39% in mycophenolate mofetil-treated and 47% and 61% in azathioprine-treated patients who were with and without one *1 allele, respectively.


CONCLUSIONS
We show that the CYP3A5*1/*3 polymorphism is an important determinant of the response to inhibition of tacrolimus metabolism by ketoconazole, with a 30% greater inhibition in those lacking *1 allele. This finding will allow better dose adjustment and minimize exposure to subtherapeutic or toxic concentrations.
Chandel
Nirupama
N
Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Aggarwal
Pardeep K
PK
Minz
Mukut
M
Sakhuja
Vinay
V
Kohli
Krishan K
KK
Jha
Vivekanand
V
D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000097:blood*
D000935:Antifungal Agents; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole; D016559:Tacrolimus