Frequency of cytochrome P450 3A4 variant genotype in transplant population and lack of association with cyclosporin clearance.
OBJECTIVE
Cytochrome P450 3A4 (CYP3A4) plays a vital role in the oxidative metabolism of many xenobiotics. Some recent reports have provided circumstantial evidence in support of an association between a genetic polymorphism (A-->G) in the 5'-flanking region (-290) of CYP3A4 and altered enzyme activity. We sought to determine whether genotyping patients for CYP3A4-G could assist with the dose optimisation of drugs metabolised by this system.


METHODS
Normal subjects and renal-transplant patients receiving cyclosporin for immune modulation were genotyped for the CYP3A4-G variant. A surrogate for cyclosporin clearance was estimated from the ratio of the cyclosporin dose, normalised for body weight and the corresponding trough concentration. The association between genotype and clearance was examined in patients who received twice-daily doses of cyclosporin and who were not on concurrent 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. The 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 corresponding value for the five patients heterozygotic for the CYP3A4-G variant 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 to a Fisher's exact test (P = 0.15).


CONCLUSIONS
Genotyping for the CYP3A4-G polymorphism is unlikely to assist cyclosporin dose selection in transplant patients.
Rivory
L P
LP
Department of Pharmacology, University of Sydney, NSW, Australia. lrivory@canc.rpa.cs.nsw.gov.au
Qin
H
H
Clarke
S J
SJ
Eris
J
J
Duggin
G
G
Ray
E
E
Trent
R J
RJ
Bishop
J F
JF
D000293:Adolescent; D000328:Adult; D000368:Aged; D001682:Biological Availability; D016572:Cyclosporine / Q000378:metabolism / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D018579:Patient Selection; D011110:Polymorphism, Genetic
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human