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Start Over Author "Price, R." Journal xenobiotica
26 results on '"Price, R."'

10. Carbamazepine: a 'blind' assessment of CYP-associated metabolism and interactions in human liver-derivedin vitrosystems

Author

Pelkonen, O., primary, Myllynen, P., additional, Taavitsainen, P., additional, Boobis, A. R., additional, Watts, P., additional, Lake, B. G., additional, Price, R. J., additional, Renwick, A. B., additional, Gómez-Lechón, M.-J., additional, Castell, J. V., additional, Ingelman-Sundberg, M., additional, Hidestrand, M., additional, Guillouzo, A., additional, Corcos, L., additional, Goldfarb, P. S., additional, and Lewis, D. F. V., additional

Published
2001
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22. Inhibition of zaleplon metabolism by cimetidine in the human liver: in vitro studies with subcellular fractions and precision-cut liver slices.

Author

Renwick, A. B., Ball, S. E., Tredger, J. M., Price, R. J., Walters, D. G., Kao, J., Scatina, J. A., and Lake, B. G.

Subjects
CIMETIDINE, HYPNOTICS
Abstract

1. The effect of cimetidine on the metabolism of zaleplon (ZAL) in human liver subcellular fractions and precision-cut liver slices was investigated. 2. ZAL was metabolized to a number of products including 5-oxo-ZAL (M2), which is known to be formed by aldehyde oxidase, N-desethyl-ZAL (DZAL), which is known to be formed by CYP3A forms, and N-desethyl-5-oxo-ZAL (M1). 3. Human liver microsomes catalysed the NADPH-dependent metabolism of ZAL to DZAL. Kinetic analysis of three microsomal preparations revealed mean (±SEM) S[sub 50] and V[sub max] of 310 ± 24 µM and 920 ± 274 pmol/min/mg protein, respectively. 4. Human liver cytosol preparations catalysed the metabolism of ZAL to M2. Kinetic analysis of three cytosol preparations revealed mean (±SEM), K[sub m] and V[sub max] of 124 ± 14 µM and 564 ± 143 pmol/min/mg protein, respectively. 5. Cimetidine inhibited ZAL metabolism to DZAL in liver microsomes and to M2 in the liver cytosol. With a ZAL substrate concentration of 62 µM, the calculated mean (±SEM, n = 3) IC50 were 596 ± 103 and 231 ± 23 µM for DZAL and M2 formation, respectively. Kinetic analysis revealed that cimetidine was a competitive inhibitor of M2 formation in liver cytosol with a mean (±SEM, n = 3) K[sub i] of 155 ± 16 µM. 6. Freshly cut human liver slices metabolized ZAL to a number of products including 1, M2 and DZAL. 7. Cimetidine inhibited ZAL metabolism in liver slices to M1 and M2, but not to DZAL. Kinetic analysis revealed that cimetidine was a competitive inhibitor of M2 formation in liver slices with an average (n = 2 preparations) K[sub i] of 506 µM. 8. The results demonstrate that cimetidine can inhibit both the CYP3A and aldehyde oxidase pathways of ZAL metabolism in the human liver. Cimetidine appears to be a more potent inhibitor of aldehyde oxidase than of CYP3A forms and hence in vivo is likely to have a more marked effect on ZAL metabolism to M2 than on DZAL formation. 9. The results also demonstrate that precision-cut liver slices may be a useful model system for in vitro drug-interaction studies. [ABSTRACT FROM AUTHOR]

Published
2002
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23. Carbamazepine: a 'blind' assessment of CYP-associated metabolism and interactions in human liver-derived in vitro systems.

Author

Pelkonen, O., Myllynen, P., Taavitsainen, P., Boobis, A. R., Watts, P., Lake, B. G., Price, R. J., Renwick, A. B., Gómez-Lechón, M.-J., Castell, J. V., Ingelman-Sundberg, M., Hidestrand, M., Guillouzo, A., Corcos, L., Goldfarb, P. S., and Lewis, D. F. V.

Subjects
AROMATASE, METABOLISM, DYNAMICS, CARBAMAZEPINE
Abstract

1. The ability of various in vitro systems for CYP enzymes (computer modelling, human liver microsomes, precision-cut liver slices, hepatocytes in culture, recombinant enzymes) to predict various aspects of in vivo metabolism and kinetics of carbamazepine (CBZ) was investigated. 2. The study was part of the EUROCYP project that aimed to evaluate relevant human in vitro systems to study drug metabolism. 3. CBZ was given to the participating laboratories without disclosing its chemical nature. 4. The most important enzyme (CYP3A4) and metabolic route (10,11-epoxidation) were predicted by all the systems studied. 5. Minor enzymes and routes were predicted to a different extent by various systems. 6. Prediction of a clearance class, i.e. slow clearance, was correctly predicted by microsomes, slices, hepatocytes and recombinant enzymes (CYP3A4). 7. The 10,11-epoxidation of CBZ by the recombinant CYP3A4 was enhanced by the addition of exogenous cytochrome-b5, leading to a considerable over-prediction. 8. Induction potency of CBZ was predicted in cultured hepatocytes in which 7- ethoxycoumarin O-deethylase was used as an index activity. 9. It seems that for a principally CYP-metabolized substance such as CBZ, all liverderived systems provide useful information for prediction of metabolic routes, rates and interactions. [ABSTRACT FROM AUTHOR]

Published
2001
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