[Effect of MDR1 polymorphic expression on oral disposition of cyclosporine A].
OBJECTIVE
To determine the relationship between C3435T mutation in exon 26 of the human multidrug resistant 1 gene and cyclosporine (CsA) pharmacokinetic (PK) parameters among healthy Chinese volunteers by nonlinear mixed effect model (NONMEM).


METHODS
Twenty healthy subjects were given orally a single dose of 500 mg CsA in microemulsion solution. Blood CsA concentrations were measured with HPLC and the genotype for the C3435T polymorphism of MDR1 gene was determined with the PCR and restriction fragment length polymorphism. The results were further confirmed by sequencing. NONMEM was performed to assess the effect of genotype on CsA PK profile.


RESULTS
MDR1 C3435T genotype was identified as the best predictor of CsA systemic exposure. The relative bioavailability of CsA was 40% higher in subjects who carried at least one 3435C allele compared to that of TT type individuals in the study population.


CONCLUSIONS
The MDR1 C3435T genotype offers a potential basis of mechanism to explain inter-subject differences in CsA oral bioavailability.
Jiao
Zheng
Z
Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, Shanghai 200040, China.
Liang
Hui-qi
HQ
Ding
Jun-jie
JJ
Li
Zhong-dong
ZD
Shi
Xiao-jin
XJ
Zhong
Ming-kang
MK
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005091:Exons; D019450:Genes, MDR / Q000235:genetics*; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D008297:Male; D009055:Mouth / Q000378:metabolism*; D011110:Polymorphism, Genetic
D016572:Cyclosporine