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Research ArticleArticle

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

J. Greg Slatter, Ping Su, James P. Sams, Larry J. Schaaf and Larry C. Wienkers
Drug Metabolism and Disposition October 1997, 25 (10) 1157-1164;
J. Greg Slatter
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Ping Su
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James P. Sams
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Larry J. Schaaf
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Larry C. Wienkers
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Abstract

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 hadKM estimates of 1.4–3.9 μM withVmax of 1.2–2.6 pmol/mg/min. The lowKM 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 α-naphthyl acetate (α-NA) was used to determine whether CPT-11 was an inhibitor of hydrolysis of high turnover substrates of carboxylesterases. Inhibition of α-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 α-naphthol formation to approximately 80% of control at α-NA concentrations of 50–800 μM. The inhibitors BNPP (360 μM) and NaF (500 μM) inhibited α-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 α-NA hydrolases. Thus, CPT-11 is unlikely to significantly inhibit high turnover, nonselective substrates of carboxylesterases.

Footnotes

  • Send reprint requests to: Dr. J. Greg Slatter, Drug Metabolism Research, Pharmacia and Upjohn Co., 301 Henrietta St., Kalamazoo MI 49007. E-mail: john.g.slatter{at}am.pnu.com.

  • ↵1 Present address: Department of Biopharmaceutical Sciences, University of California at San Francisco.

  • A preliminary account of this work was given at the 4th International ISSX Meeting, Abstracts #88, 218 and 219. Seattle WA, Aug 27–31, 1995.

  • Abbreviations used are::
    CPT
    camptothecin
    CPT-11
    irinotecan hydrochloride trihydrate
    EtOH
    ethanol
    ASA
    acetylsalicylic acid
    HMB
    hydroxymercuribenzote
    CMB
    chloromercuribenzoate
    HPLC
    high performance liquid chromatography
    KM
    Michaelis constant
    5-FU
    5-fluorouracil
    MeOH
    methanol
    BNPP
    bis-nitrophenylphosphate
    α-NA
    alpha naphthyl acetate
    SN-38
    active antineoplastic metabolite of CPT-11
    DMSO
    dimethylsulfoxide
    UPACS
    Upjohn Physical and Analytical Chemistry System
    V
    reaction velocity
    QC
    quality control standard
    [S]
    substrate concentration
    • Received March 28, 1997.
    • Accepted June 5, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 10
1 Oct 1997
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Research ArticleArticle

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

J. Greg Slatter, Ping Su, James P. Sams, Larry J. Schaaf and Larry C. Wienkers
Drug Metabolism and Disposition October 1, 1997, 25 (10) 1157-1164;

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Research ArticleArticle

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

J. Greg Slatter, Ping Su, James P. Sams, Larry J. Schaaf and Larry C. Wienkers
Drug Metabolism and Disposition October 1, 1997, 25 (10) 1157-1164;
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