Population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients

Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.

A method is presented for automated preparation of bootstrap data samples and their presentation to NONMEM for use in the validation of population pharmacokinetic or pharmacodynamic models, which have been developed with relatively small numbers of subjects. The bootstrap sampling procedure involves the use of an MS-DOS batch file and a script file for use with the public-domain text processing program, AWK, which is a single EXE file (48k in size for the version used in this report). A UNIX version of AWK is also available and UNIX users can adapt the process to their needs. Its use obviates the need for expensive, high-end statistical packages and associated script files written using in-built programming languages. The method can easily be adapted to bootstrap sampling requirements in other biomedical modelling applications.