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


CONCLUSIONS
Determination of patient plasma pNPA hydrolysis activity may have utility in predicting SN-38 pharmacokinetics during prolonged infusions of irinotecan.
Guemei
A A
AA
Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20889, USA.
Cottrell
J
J
Band
R
R
Hehman
H
H
Prudhomme
M
M
Pavlov
M V
MV
Grem
J L
JL
Ismail
A S
AS
Bowen
D
D
Taylor
R E
RE
Takimoto
C H
CH
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002091:Butyrylcholinesterase / Q000097:blood*; D002092:Butyrylthiocholine / Q000097:blood; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D002265:Carboxylic Ester Hydrolases / Q000097:blood*; D006801:Humans; D006868:Hydrolysis; D000077146:Irinotecan; D009596:Nitrophenols / Q000737:chemistry; D011237:Predictive Value of Tests
D000972:Antineoplastic Agents, Phytogenic; D009596:Nitrophenols; D002092:Butyrylthiocholine; D000077146:Irinotecan; C008642:4-nitrophenyl acetate; D002265:Carboxylic Ester Hydrolases; D002091:Butyrylcholinesterase; D002166:Camptothecin