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0090-9556/97/2510-1157-1164$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 10


ARTICLE
Bioactivation of the Anticancer Agent CPT-11 to SN-38 by Human Hepatic Microsomal Carboxylesterases and the in Vitro Assessment of Potential Drug Interactions

J. Greg Slatter, Ping Su,1 James P. Sams, Larry J. Schaaf, and Larry C. Wienkers

Drug Metabolism Research (J.G.S., P.S., J.P.S., L.C.W.) and Clinical Pharmacokinetics (L.J.S.), Pharmacia and Upjohn

Human hepatic microsomes were used to investigate the carboxylesterase-mediated bioactivation of CPT-11 to the active metabolite, SN-38. SN-38 formation velocity was determined by HPLC over a concentration range of 0.25-200 µM CPT-11. Biphasic Eadie Hofstee plots were observed in seven donors, suggesting that two isoforms catalyzed the reaction. Analysis by nonlinear least squares regression gave KM estimates of 129-164 µM with a Vmax of 5.3-17 pmol/mg/min for the low affinity isoform. The high affinity isoform had KM estimates of 1.4-3.9 µM with Vmax of 1.2-2.6 pmol/mg/min. The low KM carboxylesterase may be the main contributor to SN-38 formation at clinically relevant hepatic concentrations of CPT-11.

Using standard incubation conditions, the effects of potential inhibitors of carboxylesterase-mediated CPT-11 hydrolysis were evaluated at concentrations >=  21 µM. Positive controls bis-nitrophenylphosphate (BNPP) and physostigmine decreased CPT-11 hydrolysis to 1.3-3.3% and 23% of control values, respectively. Caffeine, acetylsalicylic acid, coumarin, cisplatin, ethanol, dexamethasone, 5-fluorouracil, loperamide, and prochlorperazine had no statistically significant effect on CPT-11 hydrolysis. Small decreases were observed with metoclopramide (91% of control), acetaminophen (93% of control), probenecid (87% of control), and fluoride (91% of control). Of the compounds tested above, based on these in vitro data, only the potent inhibitors of carboxylesterase (BNPP, physostigmine) have the potential to inhibit CPT-11 bioactivation if administered concurrently.

The carboxylesterase-mediated hydrolysis of alpha -naphthyl acetate (alpha -NA) was used to determine whether CPT-11 was an inhibitor of hydrolysis of high turnover substrates of carboxylesterases. Inhibition of alpha -NA hydrolysis by CPT-11 was determined relative to positive controls BNPP and NaF. Incubation with microsomes pretreated with CPT-11 (80-440 µM) decreased alpha -naphthol formation to approximately 80% of control at alpha -NA concentrations of 50-800 µM. The inhibitors BNPP (360 µM) and NaF (500 µM) inhibited alpha -naphthol formation to 9-10% of control and to 14-20% of control, respectively. Therefore, CPT-11-sensitive carboxylesterase isoforms may account for only 20% of total alpha -NA hydrolases. Thus, CPT-11 is unlikely to significantly inhibit high turnover, nonselective substrates of carboxylesterases.

Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1997 by the American Society for Pharmacology and Experimental Therapeutics.