Before pharmacogenomics became a common word, it was known that a small percentage of the population developed a severe reaction to azathioprine, leading to agranulocytosis and occasionally death. In the late 1980s, it was realized that this small percentage of the population had poor function of the metabolizing enzyme thiopurine S-methyltransferase (TPMT), and could only metabolize substrates, such as azathioprine, very slowly (1). The ability to predict who would have this reaction made it safer to give aziothioprine.
Azathioprine is no longer first-line therapy in transplantation, having been superceded by the calcineurin inhibitors, cyclosporine and tacrolimus. As with azathioprine, it was known that some groups of patients, especially African-Americans, tended to require higher doses of calcineurin inhibitors and had a greater incidence of rejection. Both calcineurin inhibitors are substrates for, and inhibitors of, the metabolizing enzyme cytochrome P450 3A4 and the efflux transporter P-glycoprotein (MDR1). To date, no polymorphisms of 3A4 have been proven to affect cyclosporine dosing or blood level exposure to the drug. And although a number of polymorphisms of P-glycoprotein have been found, the data on whether single polymorphisms or gene haplotypes are clinically significant are contradictory. More details on the pharmacogenetics of immunosuppressants can be found in recent reviews (2,3) by the authors of the paper appearing in this issue.
In the retrospective evaluation by MacPhee et al. (4) in this issue of the American Journal of Transplantation, the authors continue their work of demonstrating that individuals with the CYP3AP1 genotype CYP3AP1*1 have lower levels of tacrolimus, require higher doses of tacrolimus and have a higher early rejection rate, possibly due to the lower levels of tacrolimus. Similar findings have recently been reported by Zheng et al. (5) in pediatric heart transplantation. MacPhee et al. (4) note that patients with the CYP3AP1*1 allele experience a significant delay in achieving target blood levels, even when therapeutic drug monitoring is employed. As a result these authors administer a twofold higher starting tacrolimus dose to CYP3A5 expressors.
The authors suggest that knowledge of the CYP3A5 genotype could be used to guide dosing, not just of tacrolimus, but of other transplant medications such as cyclosporine and sirolimus, and more broadly for medications used in other therapies such as protease inhibitors in HIV and cancer chemotherapy agents. As with P-glycoprotein (MDR1), only further evaluation will determine if this genotype has the same effects in other organ systems, or when tested with other drug substrates.