![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 28, Issue 8, 966-972, August 2000
AstraZeneca R&D Mölndal (A.Ä., T.B.A., M.A., A.K.N.,
L.W.), Mölndal; and AstraZeneca R&D Södertälje
(I.S.), Södertälje, Sweden
This study demonstrates the stereoselective metabolism of
the optical isomers of omeprazole in human liver microsomes. The intrinsic clearance (CLint) of the formation of the hydroxy
metabolite from S-omeprazole was 10-fold lower than that
from R-omeprazole. However, the CLint value
for the sulfone and 5-O-desmethyl metabolites from
S-omeprazole was higher than that from
R-omeprazole. The sum of the CLint of the
formation of all three metabolites was 14.6 and 42.5 µl/min/mg
protein for S- and R-omeprazole,
respectively. This indicates that S-omeprazole is
cleared more slowly than R-omeprazole in vivo. The
stereoselective metabolism of the optical isomers is mediated primarily
by cytochrome P450 (CYP) 2C19, as indicated by studies using
cDNA-expressed enzymes. This is the result of a considerably higher
CLint of the 5-hydroxy metabolite formation for
R- than for S-omeprazole. For
S-omeprazole, CYP2C19 is more important for
5-O-desmethyl formation than for 5-hydroxylation. Predictions of the CLint using data from cDNA-expressed
enzymes suggest that CYP2C19 is responsible for 40 and 87% of the
total CLint of S- and
R-omeprazole, respectively, in human liver microsomes. According to experiments using cDNA-expressed enzymes, the
sulfoxidation of both optical isomers is metabolized by a single
isoform, CYP3A4. The CLint of the sulfone formation by
CYP3A4 is 10-fold higher for S-omeprazole than for
R-omeprazole, which may contribute to their
stereoselective disposition. The results of this study show that both
CYP2C19 and CYP3A4 exhibit a stereoselective metabolism of omeprazole.
CYP2C19 favors 5-hydroxylation of the pyridine group of
R-omeprazole, whereas the same enzyme mainly
5-O-demethylates S-omeprazole in the
benzimidazole group. Sulfoxidation mediated by CYP3A4 highly favors the
S-form.
This article has been cited by other articles:
|
|
 |
|
  S. Jeong, P. D. Nguyen, and Z. Desta Comprehensive In Vitro Analysis of Voriconazole Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effect on CYPs 2B6, 2C9, 2C19, and 3A Antimicrob. Agents Chemother., February 1, 2009; 53(2): 541 - 551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Abass, P. Reponen, M. Turpeinen, J. Jalonen, and O. Pelkonen Characterization of Diuron N-Demethylation by Mammalian Hepatic Microsomes and cDNA-Expressed Human Cytochrome P450 Enzymes Drug Metab. Dispos., September 1, 2007; 35(9): 1634 - 1641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Volotinen, M. Turpeinen, A. Tolonen, J. Uusitalo, J. Maenpaa, and O. Pelkonen Timolol Metabolism in Human Liver Microsomes Is Mediated Principally by CYP2D6 Drug Metab. Dispos., July 1, 2007; 35(7): 1135 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-K. Lee, J.-K. Moon, C.-H. Chang, H. Choi, H.-W. Park, B.-S. Park, H.-S. Lee, E.-C. Hwang, Y.-D. Lee, K.-H. Liu, et al. STEREOSELECTIVE METABOLISM OF ENDOSULFAN BY HUMAN LIVER MICROSOMES AND HUMAN CYTOCHROME P450 ISOFORMS Drug Metab. Dispos., July 1, 2006; 34(7): 1090 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-Q. Li, L. Weidolf, R. Simonsson, and T. B. Andersson Enantiomer/Enantiomer Interactions between the S- and R- Isomers of Omeprazole in Human Cytochrome P450 Enzymes: Major Role of CYP2C19 and CYP3A4 J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 777 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Grattagliano, P. Portincasa, M. Mastronardi, V. O Palmieri, and G. Palasciano Esomeprazole-Induced Central Fever with Severe Myalgia Ann. Pharmacother., April 1, 2005; 39(4): 757 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Q. Li, T. B. Andersson, M. Ahlstrom, and L. Weidolf COMPARISON OF INHIBITORY EFFECTS OF THE PROTON PUMP-INHIBITING DRUGS OMEPRAZOLE, ESOMEPRAZOLE, LANSOPRAZOLE, PANTOPRAZOLE, AND RABEPRAZOLE ON HUMAN CYTOCHROME P450 ACTIVITIES Drug Metab. Dispos., August 1, 2004; 32(8): 821 - 827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Mouelhi, D. J. Worley, B. Kuzmak, A. J. Destefano, and G. A. Thompson Influence of Azimilide on CYP2C19-Mediated Metabolism J. Clin. Pharmacol., April 1, 2004; 44(4): 373 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Rodrigues and P. Lu IS 17{alpha}-ETHINYL ESTRADIOL AN INHIBITOR OF CYTOCHROME P450 2C19? Drug Metab. Dispos., March 1, 2004; 32(3): 364 - 365. [Full Text] [PDF]
|
|
|
|
|
|
K.-A. Kim, M.-J. Kim, J.-Y. Park, J.-H. Shon, Y.-R. Yoon, S.-S. Lee, K.-H. Liu, J.-H. Chun, M.-H. Hyun, and J.-G. Shin STEREOSELECTIVE METABOLISM OF LANSOPRAZOLE BY HUMAN LIVER CYTOCHROME P450 ENZYMES Drug Metab. Dispos., October 1, 2003; 31(10): 1227 - 1234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. L. Kearns, T. Andersson, L. P. James, A. Gaedigk, R. A. Kraynak, S. M. Abdel-Rahman, K. Ramabadran, J. N. van den Anker, and the Pediatric Pharmacology Research Unit Network Omeprazole Disposition in Children following Single-Dose Administration J. Clin. Pharmacol., August 1, 2003; 43(8): 840 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Q. Li, A. Bjorkman, T. B. Andersson, M. Ridderstrom, and C. M. Masimirembwa Amodiaquine Clearance and Its Metabolism to N-Desethylamodiaquine Is Mediated by CYP2C8: A New High Affinity and Turnover Enzyme-Specific Probe Substrate J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 399 - 407. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
