Inhibition of intestinal microflora beta-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats.
OBJECTIVE
SN-38, a metabolite of irinotecan hydrochloride (CPT-11), is considered to play a key role in the development of diarrhea as well as in the antitumor activity of CPT-11. We have previously found that the inhibition of beta-glucuronidase, which hydrolyzes detoxified SN-38 (SN-38 glucuronide) to reform SN-38, in the lumen by eliminating the intestinal microflora with antibiotics, markedly ameliorates the intestinal toxicity of CPT-11 in rats. In this study we compared the disposition of CPT-11 and its metabolites in rats treated with and without antibiotics.


METHODS
Rats were given drinking water containing 1 mg/ml penicillin and 2 mg/ml streptomycin from 5 days before the administration of CPT-11 (60 mg/kg i.v.) and throughout the experiment. CPT-11, SN-38 glucuronide and SN-38 concentrations in the blood, intestinal tissues and intestinal luminal contents were determined by HPLC.


RESULTS
Antibiotics had little or no effect on the pharmacokinetics of CPT-11, SN-38 glucuronide or SN-38 in the blood, or in the tissues or contents of the small intestine, which has less beta-glucuronidase activity in its luminal contents. In contrast, antibiotics markedly reduced the AUC1-24 h of SN-38 (by about 85%) in the large intestine tissue without changing that of CPT-11, and this was accompanied by a complete inhibition of the deconjugation of SN-38 glucuronide in the luminal contents.


CONCLUSIONS
These results suggest that SN-38, which results from the hydrolysis of SN-38 glucuronide by beta-glucuronidase in the intestinal microflora, contributes considerably to the distribution of SN-38 in the large intestine tissue, and that inhibition of the beta-glucuronidase activity by antibiotics results in decreased accumulation of SN-38 in the large intestine.
Takasuna
K
K
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Hagiwara
T
T
Hirohashi
M
M
Kato
M
M
Nomura
M
M
Nagai
E
E
Yokoi
T
T
Kamataki
T
T
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D019540:Area Under Curve; D001419:Bacteria / Q000201:enzymology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D003967:Diarrhea / Q000382:microbiology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D007275:Injections, Intravenous; D007420:Intestine, Large / Q000187:drug effects* / Q000382:microbiology; D007421:Intestine, Small / Q000187:drug effects* / Q000382:microbiology; D000077146:Irinotecan; D008297:Male; D010406:Penicillins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013307:Streptomycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D010406:Penicillins; D000077146:Irinotecan; D005966:Glucuronidase; D002166:Camptothecin; D013307:Streptomycin