Human plasma carboxylesterase and butyrylcholinesterase enzyme activity: Correlations with SN-38 pharmacokinetics during a prolonged infusion of irinotecan

A. A. Guemei, J. Cottrell, R. Band, H. Hehman, M. Prudhomme, M. V. Pavlov, J. L. Grem, A. S. Ismail, D. Bowen, R. E. Taylor, C. H. Takimoto

Research output: Contribution to journalArticle

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Abstract

Purpose: To characterize the relationships between human plasma irinotecan carboxylesterase-converting enzyme activity, caboxylesterase-mediated hydrolysis of p-nitrophenyl acetate (pNPA), and the butyrylcholinesterase-mediated hydrolysis of butyrylthiocholine in human plasma and to test the ability of these in vitro tests to predict the variability in SN-38 pharmacokinetics in adult patients during a prolonged infusion of irinotecan. Methods: Individual plasma-converting enzyme activity was measured in 20 adult cancer patients participating in a pharmacokinetic and phase I clinical trial of a prolonged 96-h intravenous infusion of irinotecan. The pNPA and butyrylthiocholine hydrolysis in patient plasma was also assayed. Results: The irinotecan carboxylesterase-converting enzyme in human plasma had a Vmax of 89.9 ± 22.7 pmol/h per ml plasma and a Km of 207 ± 56 μM (mean ± SD, n = 3). The mean value of the specific activity of this enzyme in 20 adult cancer patients was 10.08 ± 2.96 pmol/h per ml plasma ranging from 5.43 to 15.39 pmol/h per ml. The area-under-the-concentration-versus time curve (AUC) ratio of SN-38 to irinotecan (AUCSN-38/AUCCPT-11) was used to assess the relative SN-38 exposure to the active metabolite in individual patients. Pharmacokinetic variations in the relative exposure to SN-38 did not correlate with the measured carboxylesterase-converting enzyme activity nor with plasma butyrylcholinesterase activity in our patient population. However, it did correlate with the measured pNPA hydrolysis activity in patient plasma (r2 = 0.350, P = 0.0124, n = 18). Conclusions: Determination of patient plasma pNPA hydrolysis activity may have utility in predicting SN-38 pharmacokinetics during prolonged infusions of irinotecan.

Original languageEnglish (US)
Pages (from-to)283-290
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume47
Issue number4
DOIs
StatePublished - Jan 1 2001

Fingerprint

irinotecan
Plasma (human)
Butyrylcholinesterase
Carboxylesterase
Pharmacokinetics
Enzyme activity
Enzymes
Plasmas
Hydrolysis
Butyrylthiocholine

Keywords

  • Butyrylcholinesterase
  • Carboxylesterase
  • Irinotecan
  • SN-38

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Human plasma carboxylesterase and butyrylcholinesterase enzyme activity : Correlations with SN-38 pharmacokinetics during a prolonged infusion of irinotecan. / Guemei, A. A.; Cottrell, J.; Band, R.; Hehman, H.; Prudhomme, M.; Pavlov, M. V.; Grem, J. L.; Ismail, A. S.; Bowen, D.; Taylor, R. E.; Takimoto, C. H.

In: Cancer Chemotherapy and Pharmacology, Vol. 47, No. 4, 01.01.2001, p. 283-290.

Research output: Contribution to journalArticle

Guemei, AA, Cottrell, J, Band, R, Hehman, H, Prudhomme, M, Pavlov, MV, Grem, JL, Ismail, AS, Bowen, D, Taylor, RE & Takimoto, CH 2001, 'Human plasma carboxylesterase and butyrylcholinesterase enzyme activity: Correlations with SN-38 pharmacokinetics during a prolonged infusion of irinotecan', Cancer Chemotherapy and Pharmacology, vol. 47, no. 4, pp. 283-290. https://doi.org/10.1007/s002800000258
Guemei, A. A. ; Cottrell, J. ; Band, R. ; Hehman, H. ; Prudhomme, M. ; Pavlov, M. V. ; Grem, J. L. ; Ismail, A. S. ; Bowen, D. ; Taylor, R. E. ; Takimoto, C. H. / Human plasma carboxylesterase and butyrylcholinesterase enzyme activity : Correlations with SN-38 pharmacokinetics during a prolonged infusion of irinotecan. In: Cancer Chemotherapy and Pharmacology. 2001 ; Vol. 47, No. 4. pp. 283-290.
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abstract = "Purpose: To characterize the relationships between human plasma irinotecan carboxylesterase-converting enzyme activity, caboxylesterase-mediated hydrolysis of p-nitrophenyl acetate (pNPA), and the butyrylcholinesterase-mediated hydrolysis of butyrylthiocholine in human plasma and to test the ability of these in vitro tests to predict the variability in SN-38 pharmacokinetics in adult patients during a prolonged infusion of irinotecan. Methods: Individual plasma-converting enzyme activity was measured in 20 adult cancer patients participating in a pharmacokinetic and phase I clinical trial of a prolonged 96-h intravenous infusion of irinotecan. The pNPA and butyrylthiocholine hydrolysis in patient plasma was also assayed. Results: The irinotecan carboxylesterase-converting enzyme in human plasma had a Vmax of 89.9 ± 22.7 pmol/h per ml plasma and a Km of 207 ± 56 μM (mean ± SD, n = 3). The mean value of the specific activity of this enzyme in 20 adult cancer patients was 10.08 ± 2.96 pmol/h per ml plasma ranging from 5.43 to 15.39 pmol/h per ml. The area-under-the-concentration-versus time curve (AUC) ratio of SN-38 to irinotecan (AUCSN-38/AUCCPT-11) was used to assess the relative SN-38 exposure to the active metabolite in individual patients. Pharmacokinetic variations in the relative exposure to SN-38 did not correlate with the measured carboxylesterase-converting enzyme activity nor with plasma butyrylcholinesterase activity in our patient population. However, it did correlate with the measured pNPA hydrolysis activity in patient plasma (r2 = 0.350, P = 0.0124, n = 18). Conclusions: Determination of patient plasma pNPA hydrolysis activity may have utility in predicting SN-38 pharmacokinetics during prolonged infusions of irinotecan.",
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T1 - Human plasma carboxylesterase and butyrylcholinesterase enzyme activity

T2 - Correlations with SN-38 pharmacokinetics during a prolonged infusion of irinotecan

AU - Guemei, A. A.

AU - Cottrell, J.

AU - Band, R.

AU - Hehman, H.

AU - Prudhomme, M.

AU - Pavlov, M. V.

AU - Grem, J. L.

AU - Ismail, A. S.

AU - Bowen, D.

AU - Taylor, R. E.

AU - Takimoto, C. H.

PY - 2001/1/1

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N2 - Purpose: To characterize the relationships between human plasma irinotecan carboxylesterase-converting enzyme activity, caboxylesterase-mediated hydrolysis of p-nitrophenyl acetate (pNPA), and the butyrylcholinesterase-mediated hydrolysis of butyrylthiocholine in human plasma and to test the ability of these in vitro tests to predict the variability in SN-38 pharmacokinetics in adult patients during a prolonged infusion of irinotecan. Methods: Individual plasma-converting enzyme activity was measured in 20 adult cancer patients participating in a pharmacokinetic and phase I clinical trial of a prolonged 96-h intravenous infusion of irinotecan. The pNPA and butyrylthiocholine hydrolysis in patient plasma was also assayed. Results: The irinotecan carboxylesterase-converting enzyme in human plasma had a Vmax of 89.9 ± 22.7 pmol/h per ml plasma and a Km of 207 ± 56 μM (mean ± SD, n = 3). The mean value of the specific activity of this enzyme in 20 adult cancer patients was 10.08 ± 2.96 pmol/h per ml plasma ranging from 5.43 to 15.39 pmol/h per ml. The area-under-the-concentration-versus time curve (AUC) ratio of SN-38 to irinotecan (AUCSN-38/AUCCPT-11) was used to assess the relative SN-38 exposure to the active metabolite in individual patients. Pharmacokinetic variations in the relative exposure to SN-38 did not correlate with the measured carboxylesterase-converting enzyme activity nor with plasma butyrylcholinesterase activity in our patient population. However, it did correlate with the measured pNPA hydrolysis activity in patient plasma (r2 = 0.350, P = 0.0124, n = 18). Conclusions: Determination of patient plasma pNPA hydrolysis activity may have utility in predicting SN-38 pharmacokinetics during prolonged infusions of irinotecan.

AB - Purpose: To characterize the relationships between human plasma irinotecan carboxylesterase-converting enzyme activity, caboxylesterase-mediated hydrolysis of p-nitrophenyl acetate (pNPA), and the butyrylcholinesterase-mediated hydrolysis of butyrylthiocholine in human plasma and to test the ability of these in vitro tests to predict the variability in SN-38 pharmacokinetics in adult patients during a prolonged infusion of irinotecan. Methods: Individual plasma-converting enzyme activity was measured in 20 adult cancer patients participating in a pharmacokinetic and phase I clinical trial of a prolonged 96-h intravenous infusion of irinotecan. The pNPA and butyrylthiocholine hydrolysis in patient plasma was also assayed. Results: The irinotecan carboxylesterase-converting enzyme in human plasma had a Vmax of 89.9 ± 22.7 pmol/h per ml plasma and a Km of 207 ± 56 μM (mean ± SD, n = 3). The mean value of the specific activity of this enzyme in 20 adult cancer patients was 10.08 ± 2.96 pmol/h per ml plasma ranging from 5.43 to 15.39 pmol/h per ml. The area-under-the-concentration-versus time curve (AUC) ratio of SN-38 to irinotecan (AUCSN-38/AUCCPT-11) was used to assess the relative SN-38 exposure to the active metabolite in individual patients. Pharmacokinetic variations in the relative exposure to SN-38 did not correlate with the measured carboxylesterase-converting enzyme activity nor with plasma butyrylcholinesterase activity in our patient population. However, it did correlate with the measured pNPA hydrolysis activity in patient plasma (r2 = 0.350, P = 0.0124, n = 18). Conclusions: Determination of patient plasma pNPA hydrolysis activity may have utility in predicting SN-38 pharmacokinetics during prolonged infusions of irinotecan.

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KW - Carboxylesterase

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