# ETOPOSIDE PHARMACOLOGY AND METABOLISM

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 1987 · $90,282

## Abstract

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.

## Key facts

- **NIH application ID:** 3178996
- **Project number:** 5R01CA039686-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **SAM.gov UEI:** GTNBNWXJ12D5
- **Principal Investigator:** Kenneth R Hande
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $90,282
- **Award type:** 5
- **Project period:** 1985-09-01 → 1988-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178996

## Citation

> US National Institutes of Health, RePORTER application 3178996, ETOPOSIDE PHARMACOLOGY AND METABOLISM (5R01CA039686-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3178996. Licensed CC0.

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