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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

The Contribution of Intestinal UDP-Glucuronosyltransferases in Modulating 7-Ethyl-10-hydroxy-camptothecin (SN-38)-Induced Gastrointestinal Toxicity in Rats

University of North Carolina at Chapel Hill Schools of Pharmacy (M.N.T., X.T., P.C.S.) and Medicine (J.N.N.), Chapel Hill, North Carolina; and Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (K.K.M., F.K.K., J.K.R.)

Life-threatening diarrhea afflicts a considerable percentage of patients treated with irinotecan, an anticancer agent with effects elicited through its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). The primary detoxification pathway for SN-38 is glucuronidation. The purpose of this study was to evaluate the role that intestinal UDP-glucuronosyltransferases (UGTs) have from hepatic UGTs in modulating this diarrhea. To investigate this, Gunn rats devoid of UGT1A activity were injected with recombinant adenoviral vectors expressing UGT1A1, 1A6, and 1A7, resulting in reconstituted hepatic UGT expression comparable to a heterozygote. Hepatic microsome studies indicated that 4 to 7 days after adenoviral injection, transfected Gunn rats (j/jAV) had SN-38 glucuronide (SN-38G) formation rates three times higher than control heterozygote rats (j+AV). The adenovirus did not impart any glucuronidating capacity to the intestine in j/jAV rats, whereas j+AV rats possessed intestinal UGT function. After the administration of 20 mg/kg/day irinotecan i.p. to j/jAV rats 4 days after adenovirus injection, diarrhea ensued before the fourth irinotecan dose. j+AV rats were spared the diarrhea, and the toxicity was mild compared with the j/jAV rats, as measured by diarrhea scores, weight loss, and histological assessments of the cecum and colon. The pharmacokinetics of irinotecan, SN-38, and SN-38G indicate that the systemic exposure of SN-38 and SN-38G was higher and lower, respectively, in j/jAV rats. Despite this, the biliary excretion of irinotecan and metabolites was similar. Because intestinal UGTs are the main discriminating factor between j/jAV and j+AV rats, their presence seems to be critical for the gastrointestinal protection observed in j+AV rats.

Address correspondence to: Dr. Philip C. Smith, 1309 Kerr Hall, CB 7360, University of North Carolina, Chapel Hill, NC 27599. E-mail: pcs{at}email.unc.edu