Biomedical subjects
Publications and source records attributed to A Durand.
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An individual dose adaptation for cisplatin (CDDP), etoposide and gallium chloride (GaCl3) was proposed to improve the efficacy of this combination chemotherapy and avoid its toxicity. A clinical study was performed in 28 non small cell lung cancer patients, to verify this hypothesis. CDDP and etoposide were administered as continuous infusions every 3 weeks and GaCl3 orally during and between the CDDP-etoposide sequential infusions. CDDP doses were adjusted to achieve, during each 5 day infusion, an area under the total plasma platinum concentrations versus time curve (AUC Pt 0-120) ranging between 80,000 and 100,000 micrograms/l.h. Etoposide dosages were 120 mg/24 h during days 1-3 of the CDDP infusion. GaCl3 dosages were adjusted to obtain plasma gallium (Ga) concentrations ranging between 200 and 400 micrograms/l. The proposed methods of adaptation were successful from a pharmacokinetic point of view as AUC Pt 0-120 were respectively 81351 +/- 4788, 88268 +/- 8451 and 88331 +/- 8778 micrograms/l.h during the first 3 courses, and plasma Ga concentrations, determined during the 2nd and 3rd CDDP courses, 16 hours after the beginning of the CDDP infusion, were respectively 264 +/- 127 and 313 +/- 186 micrograms/l. However, these results were not pharmacodynamically successful and the therapeutic window was not confirmed. Past clinical trials with GaCl3 will be reviewed, as well as the factors which modify the pharmacokinetics or the pharmacodynamic effects of CDDP and GaCl3. From this review, an optimal dosage of 400 mg GaCl3 could be proposed to potentiate a combination chemotherapy with a platinum compound. The target AUC of the platinum compound should be the AUC avoiding its cumulative toxicity.
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.
The properties of UDP-glucuronosyltransferase (UDPGT) toward digitoxigenin-monodigitoxoside (DT1) have been studied in human liver microsomes. The enzyme activity determined in nonactivated microsomes was very low (20 pmol/min/mg protein) compared with previously published values in rats (104 pmol/min/mg protein) or mice (379 pmol/min/mg protein) DT1-UDPGT activity was increased (180 to 220% of control activity) by Lubrol PX, Triton X-100, or (3-[3-cholamidopropyl]dimethylammonio)-1-propane sulfonic acid. The rate of DT1 glucuronidation determined for 29 different human liver microsomes was variable (18 to 87 pmol/min/mg protein). The KM found was approximately 4.5 microM. DT1-UDPGT activity was tentatively correlated with other known UDPGT activities. No significant correlations were found between DT1 and p-nitrophenol or 4-hydroxybiphenyl UDPGT activities. On the other hand, a strong correlation (r = 0.64, p < 0.05) was observed between DT1-UDPGT activity and digoxigenin-monodigitoxoside (DG1, another cardiac glycoside) glucuronidation rate.
The metabolism of zidovudine (AZT) and its modulating factors have been studied in human liver microsomes. In a first step, we demonstrated the involvement of UDP-glucoronosyltransferase (UDPGT) 2 form in AZT glucuronidation. In a second step, in order to predict drug interactions, we screened the effect of 52 drugs, representative of 17 different therapeutic classes, on AZT glucuronidation. We demonstrated that about twenty molecules glucuronidated or not are able to inhibit AZT glucuronidation. Finally, the NADPH-dependent reductive metabolism of AZT which produced a toxic metabolite, 3'-amino-3'-deoxythymidine (AMT) has been studied. Our studies demonstrated that AMT was formed only under anaerobic conditions and that its formation is catalysed by the NADPH-cytochrome P450 reductase.
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