Pharmacokinetic modulation of irinotecan metabolites by sulphobromophthalein in rats.
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.
Itoh
Tatsuya
T
Department of Pharmacy, Sapporo Social Insurance General Hospital, Chuo-2-jo, 6-chome, Atsubetsu-ku, Sapporo 004-8618, Japan.
Itagaki
Shirou
S
Sasaki
Kentaro
K
Hirano
Takeshi
T
Takemoto
Isao
I
Iseki
Ken
K
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001646:Bile / Q000187:drug effects; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood* / Q000378:metabolism* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D020719:Glucuronides / Q000097:blood*; D000077146:Irinotecan; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013448:Sulfobromophthalein / Q000494:pharmacology*
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D013448:Sulfobromophthalein; D000077146:Irinotecan; D002166:Camptothecin