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 used in combination with other drugs for the treatment of acquired immune deficiency syndrome (AIDS) or AIDS-related complex diseases, drug interaction studies are required to improve the efficiency or decrease the toxicity of this antiviral drug. Although AZT is extensively metabolized as 5'-O-glucuronide (GAZT), we have recently demonstrated that many drugs that are or are not glucuronidated could be involved in relevant interactions. In this article, we screened the effect of 16 anticancer drugs on the glucuronidation of AZT by human liver microsome. Our results demonstrate that six anticancer drugs inhibit the in vitro formation of GAZT. Cyclophosphamide, ifosfamide, methotrexate, and etoposide are competitive inhibitors, whereas navelbine and vinblastine are noncompetitive inhibitors of AZT glucuronidation. Their estimated apparent Ki values ranged from 0.3 mM for navelbine to 9.8 mM for methotrexate. For compounds that competitively inhibit the in vitro formation of GAZT, theoretical percentages of inhibition obtainable in vivo at clinically relevant plasma concentrations of the coadministered drugs were determined. By considering these parameters, the rank order of these drugs with respect to their potential inhibition is cyclophosphamide >> ifosfamide > methotrexate = etoposide. Because the peak physiological concentrations (usual expected plasma levels) of ifosfamide, methotrexate, and etoposide are considerably less than their Ki values, only cyclophosphamide should inhibit the in vivo hepatic glucuronidation of AZT. Complementary clinical pharmacokinetic studies should be useful to confirm these findings.
Rajaonarison
J F
JF
Laboratoire de Toxicologie et Pharmacie Clinique, Faculté de Pharmacie, Marseille, France.
Lacarelle
B
B
Catalin
J
J
Durand
A
A
Cano
J P
JP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D005965:Glucuronates; D015215:Zidovudine; C055886:3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine