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

• Published in: Cancer chemotherapy and pharmacology 2001-04, Vol.47 (4), p.283-290
• Main Authors: GUEMEI, Aida A, COTTRELL, Jeff, TAKIMOTO, Chris H, BAND, Roger, HEHMAN, Hilary, PRUDHOMME, Mike, PAVLOV, Michael V, GREM, Jean L, ABDEL SALAM ISMAIL, BOWEN, Donnell, TAYLOR, Robert E
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacokinetics; Area Under Curve; Biological and medical sciences; Butyrylcholinesterase - blood; Butyrylthiocholine - blood; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Carboxylic Ester Hydrolases - blood; Chemotherapy; Humans; Hydrolysis; Medical sciences; Nitrophenols - chemistry; Pharmacology. Drug treatments; Predictive Value of Tests
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002800000258

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. 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. 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 microM (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). Determination of patient plasma pNPA hydrolysis activity may have utility in predicting SN-38 pharmacokinetics during prolonged infusions of irinotecan.