Factors involved in prolongation of the terminal disposition phase of SN-38: clinical and experimental studies.
The active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxycamptothecin (SN-38), is either formed through enzymatic cleavage of CPT-11 by carboxyl esterases (CEs) or through cytochrome P-450 3A-mediated oxidation to 7-ethyl-10-[4-(1-piperidino)-1-amino] carbonyloxycamptothecin (NPC) and a subsequent conversion by CE. In the liver, SN-38 is glucuronidated (SN-38G) by UGT1A1, which also conjugates bilirubin. Fourteen patients were treated with 350 mg/m2 CPT-11, and we performed pharmacokinetic analysis during a 500-h collection period. The half-life and area under the plasma concentration-time curve of SN-38 were 47+/-7.9 h and 2.0+/-0.79 microM x h, respectively, both representing a 2-fold increase as compared with earlier reported estimates (A. Sparreboom et al, Clin. Cancer Res., 4: 2747-2754, 1998). As an explanation for this phenomenon, we noted substantial formation of SN-38 from CPT-11 and NPC by plasma CE, consistent with the low circulating levels of NPC observed. In addition, transport studies in Caco-2 monolayers indicated that nonglucuronidated SN-38 could cross the membrane from apical to basolateral, indicating the potential for recirculation processes that can prolong circulation times. Interestingly, individual levels of fecal beta-glucuronidase, which is known to mediate SN-38G hydrolysis, were not related to any of the SN-38 kinetic parameters (r = 0.09; P = 0.26), suggesting that interindividual variation in this enzyme is unimportant in explaining SN-38 pharmacokinetic variability. We have also found, in contrast to earlier data, that SN-38G/SN-38 plasma concentration ratios decrease over time from approximately 7 (up to 50 h) to approximately 1 (at 500 h). This decrease could be explained by the fact that glucuronidation of SN-38 and bilirubin is increasingly competitive at lower drug levels. In addition, no evidence was found for SN-38G transport through the Caco-2 cells. Our findings indicate that until now the circulation time of SN-38 has been underestimated. This is of crucial importance to our understanding of the clinical action of CPT-11 and for future pharmacokinetic/pharmacodynamic relationships.
Kehrer
D F
DF
Department of Medical Oncology, Daniel den Hoed Kliniek, Rotterdam Cancer Institute and University Hospital Rotterdam, The Netherlands.
Yamamoto
W
W
Verweij
J
J
de Jonge
M J
MJ
de Bruijn
P
P
Sparreboom
A
A
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D018938:Caco-2 Cells / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D002265:Carboxylic Ester Hydrolases / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D005243:Feces / Q000201:enzymology; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D005966:Glucuronidase; D002166:Camptothecin