Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital.
OBJECTIVE
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.
Gupta
E
E
Department of Medicine, University of Chicago Medical Center, IL 60637, USA.
Wang
X
X
Ramirez
J
J
Ratain
M J
MJ
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D001711:Biotransformation / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D000077146:Irinotecan; D008657:Metabolic Clearance Rate; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; D014635:Valproic Acid; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D002166:Camptothecin; D010634:Phenobarbital