Pharmacokinetic modulation of irinotecan metabolites by sulphobromophthalein in rats

• Published in: Journal of pharmacy and pharmacology Vol. 56; no. 6; p. 809
• Main Authors: Itoh, Tatsuya, Itagaki, Shirou, Sasaki, Kentaro, Hirano, Takeshi, Takemoto, Isao, Iseki, Ken
• Format: Journal Article
• Language: English
• Published: England 01.06.2004
• Subjects: Animals; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - blood; Antineoplastic Agents, Phytogenic - pharmacokinetics; Area Under Curve; Bile - drug effects; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - blood; Camptothecin - metabolism; Camptothecin - pharmacokinetics; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Glucuronides - blood; Male; Rats; Rats, Wistar; Sulfobromophthalein - pharmacology
• ISSN: 0022-3573
• DOI: 10.1211/0022357023420

The purpose of this study was to modulate the pharmacokinetics of irinotecan metabolites, SN-38 and SN-38-glucuronide, by possibly reducing biliary excretion, which in turn could lower irinotecan toxicity. SN-38-glucuronide is associated with severe diarrhoea that occurs after irinotecan therapy as a result of enteric injury caused by SN-38. Sulphobromophthalein is used clinically as a drug for testing liver function and is considered to be a safe drug. We investigated the effect of sulphobromophthalein on the disposition of irinotecan metabolites after CPT-11 (7-ethyl-10-[10-4-(1-piperidino)-1-piperidino]-carbonyloxy-camptothecin) administration. Wistar rats were administered CPT11 (500 microg/body) in saline as a bolus injection into the femoral vein through a catheter. The volume of drug solution injected into each animal was 1 mL. Rats were either administered CPT-11 alone or simultaneously with sulphobromophthalein (20 mg/body). After administration, blood and bile samples were taken at appropriate intervals and analysed by HPLC. Co-administration of sulphobromophthalein partially inhibited the biliary excretion of SN-38-glucuronide with a concomitant increase in its area under the plasma concentration-time curve (AUC) but did not significantly alter the biliary excretion and AUC of the active metabolite SN-38. These results suggested that cotreatment of CPT-11 with sulphobromophthalein might decrease intraluminal SN-38 concentrations without altering the pharmacokinetics of SN-38.