Cysteine effects on the pharmacokinetics of etoposide in protein–calorie malnutrition rats: increased gastrointestinal absorption by cysteine

Abstract

1. Protein–calorie malnutrition (PCM) occurs frequently in advanced cancer patients and has a profound impact on the toxicity of many drugs. Thus, the pharmacokinetics of etoposide were evaluated in control, control with cysteine (CC), PCM, and PCM with cysteine (PCMC) rats.

2. Etoposide was administered intravenously (2 mg/kg) or orally (10 mg/kg). Changes in hepatic and intestinal cytochrome P450s (CYPs) and effects of cysteine on intestinal P-glycoprotein (P-gp)-mediated efflux were also measured.

3. In PCM rats, the CL_NR (AUC_0–∞) of intravenous etoposide was significantly slower (greater) than that in controls, because of the significant decrease in the hepatic CYP3A subfamily and P-gp. In PCMC rats, the slowed CL_NR of etoposide in PCM rats was restored to the control level by cysteine treatment. PCMC rats showed a significantly greater AUC_{0–6 h} of oral etoposide than PCM rats, primarily because of the increased gastrointestinal absorption of etoposide as a result of the inhibition of intestinal P-gp by cysteine.

4. The gastrointestinal absorption of an oral anticancer drug, which is a substrate of P-gp, may be improved by co-administration of cysteine in advanced cancer patients if the present rat data can be extrapolated to patients.

Keywords::

• Etoposide
• pharmacokinetics
• protein–calorie malnutrition
• cysteine
• CYP
• P-gp