EFFECT OF ANTICANCER DRUGS ON THE GLUCURONIDATION OF 3'-AZIDO-3'-DEOXYTHYMIDINE IN HUMAN LIVER-MICROSOMES

Because zidovudine (3'-azido-3'-deoxythymidine or AZT) is frequently u sed in combination with other drugs for the treatment of acquired immu ne deficiency syndrome (AIDS) or AIDS-related complex diseases, drug i nteraction studies are required to improve the efficiency or decrease the toxicity of this antiviral drug. Although AZT is extensively metab olized as 5'-O-glucuronide (GAZT), we have recently demonstrated that many drugs that are or are not glucuronidated could be involved in rel evant interactions. In this article, we screened the effect of 16 anti cancer drugs on the glucuronidation of AZT by human liver microsome. O ur results demonstrate that six anticancer drugs inhibit the in vitro formation of GAZT. Cyclophosphamide, ifosfamide, methotrexate, and eto poside are competitive inhibitors, whereas navelbine and vinblastine a re noncompetitive inhibitors of AZT glucuronidation. Their estimated a pparent K(i) values ranged from 0.3 mM for navelbine to 9.8 mM for met hotrexate. For compounds that competitively inhibit the in vitro forma tion of GAZT, theoretical percentages of inhibition obtainable in vivo at clinically relevant plasma concentrations of the coadministered dr ugs were determined. By considering these parameters, the rank order o f these drugs with respect to their potential inhibition is cyclophosp hamide >> ifosfamide > methotrexate = etoposide. Because the peak phys iological concentrations (usual expected plasma levels) of ifosfamide, methotrexate, and etoposide are considerably less than their K(i) val ues, only cyclophosphamide should inhibit the in vivo hepatic glucuron idation of AZT. Complementary clinical pharmacokinetic studies should be useful to confirm these findings.