Document Detail

Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital.
MedLine Citation:
PMID:  9054958     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Irinotecan (CPT-11) is hydrolyzed to its active metabolite SN-38 which is subsequently conjugated by uridine diphosphate glucuronosyl transferase (UDP-GT) to the glucuronide (SN-38G). Both preclinical and clinical data indicate that conjugation is a primary clearance mechanism for SN-38 with the plasma glucuronide levels being substantially higher than those of SN-38. This investigation was designed to determine the possibility of modulation of glucuronidation of SN-38 and its effect on the disposition of the parent drug and metabolites. METHODS: Female Wistar rats were pretreated with 200 mg/kg valproic acid (VPA), an inhibitor of glucuronidation, 5 min prior to the administration of 20 mg/kg irinotecan. The control rats were given 20 mg/kg irinotecan only. To study the effect of inducers of UDP-GT activity, rats were pretreated with phenobarbital (PB) before irinotecan administration. RESULTS: Pretreatment with VPA caused a 99% inhibition in the formation of SN-38G leading to a 270% increase in the area under plasma concentration-time curve (AUC) of SN-38 compared with the control rats. The irinotecan estimations were unchanged in the two groups. PB pretreatment caused a 1.7-fold increase in the AUC of SN-38G and a concomitant 31% and 59% reduction in the AUCs of SN-38 and irinotecan, respectively. CONCLUSIONS: The most plausible explanation for the alterations in SN-38G disposition is inhibition of SN-38 conjugation by VPA and induction of the conjugation by PB.
E Gupta; X Wang; J Ramirez; M J Ratain
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  39     ISSN:  0344-5704     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  1997  
Date Detail:
Created Date:  1997-03-28     Completed Date:  1997-03-28     Revised Date:  2007-09-25    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  440-4     Citation Subset:  IM    
Department of Medicine, University of Chicago Medical Center, IL 60637, USA.
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MeSH Terms
Antineoplastic Agents, Phytogenic / pharmacokinetics
Biotransformation / drug effects
Camptothecin / analogs & derivatives*,  pharmacokinetics
Glucuronates / metabolism*
Glucuronosyltransferase / metabolism
Metabolic Clearance Rate
Phenobarbital / pharmacology*
Rats, Wistar
Valproic Acid / pharmacology*
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Glucuronates; 100286-90-6/irinotecan; 50-06-6/Phenobarbital; 7689-03-4/Camptothecin; 99-66-1/Valproic Acid; EC

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