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Polymorphisms of CYP3A5 Affect Serum Levels and Maintenance Doses of Tacrolimus in Myasthenia Gravis Patients

Kawaguchi N, Nakatani K, Uzawa A, Nemoto Y, Himuro K,Kuwabara S

Objectives: To evaluate the influences of polymorphisms of cytochrome P450 (CYP) 3A5 (A6986G, CYP3A5*3) on serum levels of tacrolimus and cyclosporine (CyA) in patients with myasthenia gravis (MG).
Methods: This study included 74 MG patients treated with tacrolimus (n=65) or CyA (n=22). Genomic DNA was extracted and amplified with specific primers, and CYP3A5 alleles were confirmed by direct sequencing of PCR products on an automated AB13100 DNA sequencer. We measured blood trough level (C0) of tacrolimus and CyA. Clinical disabilities were evaluated with the MG-ADL scale.
Results: For tacrolimus C0, the CYP3A5*3/*3 genotype was associated with higher levels than the CYP3A5*1/*3 genotypes (7.1 ng/ml versus 2.9 ng/ml; P<0.0001) and CYP3A*1/*1 (7.1 ng/ml versus 1.3 ng/ml; P<0.0004). The improvement in the mean MG-ADL scores tended to be better in MG patients with the CYP3A5*3/*3 or CYP3A5*1/*3 than those with CYP3A5*1/*1. For the CyA concentrations, CYP3A5 genotypes did not have significant effects.
Conclusion: In MG patients, CYP3A5 polymorphism significantly affects serum levels of tacrolimus and thereby treatment effects, but not those of CyA. The maintenance dose of tacrolimus should be determined considering CYP3A5 polymorphism.