Etopside or VP-16 is a antineoplastic agent recently approved by the FDA for commercial use. In clinical trials etoposide has been a very effective agent in the treatment of germinal malignancies, small cell lung cancer and several types of lymphoma. With this demonstrated activity, clinical use of etoposide will probably expand over the next few years. However, the pharmacology of this drug has yet to be adequately defined. One-third of an administered dose of etoposide is cleared through the kidney as intact drug. The remaining two-thirds appears to be metabolized with the liver likely to be the primary site of such metabolism. The amount of metabolite formed and the specific enzyme system involved in etoposide's metabolism are not known. Since metabolism is likely to convert active drug to an inactive metabolite, impairment of etoposide metabolism may result in increased toxicity to normal tissues including the bone marrow and gastrointestinal tract. To optimally use this important, active drug, a better understanding of its pharmacology is needed. Studies are proposed to quantitate the formation of two identified etoposide metabolites (the cis-picro lactone and hydroxy acid derivatives) in the blood and urine of a series of patients with normal renal and hepatic function. Similar studies are planned for patients with hepatic function impairment (serum billirubin greater than 2.0 mg/dl) to determine guidelines for adjusting drug doses in such patients to prevent excess toxicity. In vitro studies using isolated hepatic enzymes will be conducted to determine which enzyme system (carboxyesterase, mixed function oxidase, or debrizoquine hydroxylase) converts etoposide to its major metabolite, the inactive hydroxy acid derivative. In vitro studies of rats will be performed to see if etoposide undergoes enterohepatic circulation and whether sterilization of gut flora by antibiotics alters the metabolism of etoposide. Finally, the impact of etoposide on inhibition of hepatic microsonal function will be measured in a rat model by determining etoposide's effects on the clearance of two test drugs of microsomal oxidative metabolism, aminopyrine and hexamethylmelamine.
| Hande, K R; Wolff, S N; Greco, F A et al. (1990) Etoposide kinetics in patients with obstructive jaundice. J Clin Oncol 8:1101-7 |
| Hande, K; Bennett, R; Hamilton, R et al. (1988) Metabolism and excretion of etoposide in isolated, perfused rat liver models. Cancer Res 48:5692-5 |
| Hande, K; Anthony, L; Hamilton, R et al. (1988) Identification of etoposide glucuronide as a major metabolite of etoposide in the rat and rabbit. Cancer Res 48:1829-34 |
| Wolff, S N; Grosh, W W; Prater, K et al. (1987) In vitro pharmacodynamic evaluation of VP-16-213 and implications for chemotherapy. Cancer Chemother Pharmacol 19:246-9 |
