![[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. 27, Issue 2, 173-179, February 1999
Department of Biopharmaceutical Sciences, School of Pharmacy,
University of California at San Francisco, San Francisco,
California (W.J., L.M., L.Z.B., U.C.);
Institut für
Allgemeine Pharmakologie, Medizinische Hochschule Hannover, Hannover,
Germany (G.K., K.H., I.H., K.-F.S.); and
Institut für
Pharmakologie und Toxikologie, Universität Rostock, Germany
(M.D.)
In an in vitro study, the cytochrome P-450 3A (CYP3A)-dependent
metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-Co A
reductase inhibitors lovastatin and pravastatin were compared. Lovastatin was metabolized by human liver microsomes to two major metabolites: 6'
-hydroxy [Michaelis-Menten constant
(Km): 7.8 ± 2.7 µM] and
6'-exomethylene lovastatin (Km,10.3 ± 2.6 µM). 6'-Hydroxylovastatin formation in the liver was
inhibited by the specific CYP3A inhibitors cyclosporine
(Ki, 7.6 ± 2.3 µM), ketoconazole
(Ki, 0.25 ± 0.2 µM), and
troleandomycin (Ki, 26.6 ± 18.5 µM).
Incubation of pravastatin with human liver microsomes resulted in the
generation of 3'
,5',6'-trihydroxy pravastatin
(Km, 4,887 ± 2,185 µM) and hydroxy
pravastatin (Km, 20,987 ± 9,389 µM). The formation rates of 3',5',6'-trihydroxy pravastatin by reconstituted CYP3A enzymes were (1,000 µM
pravastatin) 1.9 ± 0.6 pmol·min
1·pmol CYP3A4
and 0.06 ± 0.04 pmol·min1·pmol CYP3A5, and the
formation rates of hydroxy pravastatin were 0.12 ± 0.02 pmol·min1·pmol CYP3A4 and 0.02 ± 0.004 pmol·min1·pmol CYP3A5. The specific CYP3A inhibitors
cyclosporine, ketoconazole, and troleandomycin significantly inhibited
hydroxy pravastatin formation by human liver microsomes, but only
ketoconazole inhibited 3',5',6'-trihydroxy pravastatin
formation, suggesting that other CYP enzymes are involved in its
formation. It is concluded that, compared with lovastatin
[CLint formation 6'-hydroxylovastatin (µl·min1·mg1): 199 ± 248, 6'-exomethylene lovastatin: 138 ± 104)], CYP3A-dependent metabolism of pravastatin [CLint formation
3',5',6'-trihydroxy pravastatin
(µl·min1·mg1): 0.03 ± 0.03 and
hydroxy pravastatin: 0.02 ± 0.02] is a minor elimination
pathway. In contrast to lovastatin, drug interactions with pravastatin
CYP3A-catalyzed metabolism cannot be expected to have a clinically
significant effect on its pharmacokinetics.
This article has been cited by other articles:
|
|
 |
|
  R. Kupfer, L. Swanson, S. Chow, R. E. Staub, Y. L. Zhang, I. Cohen, and U. Christians Oxidative in Vitro Metabolism of Liquiritigenin, a Bioactive Compound Isolated from the Chinese Herbal Selective Estrogen {beta}-Receptor Agonist MF101 Drug Metab. Dispos., November 1, 2008; 36(11): 2261 - 2269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, T. Koster, C. Morike, S. v. Horsten, U. Martin, M. Bader, A. Haverich, and A. R. Simon Pravastatin prolongs graft survival in an allogeneic rat model of orthotopic single lung transplantation. Eur. J. Cardiothorac. Surg., September 1, 2006; 30(3): 515 - 524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Nowack and B. Nowak Herbal teas interfere with cyclosporin levels in renal transplant patients Nephrol. Dial. Transplant., November 1, 2005; 20(11): 2554 - 2556. [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Gustavson, S. M. Schweitzer, S. Koehne-Voss, R. Achari, T. O. Chira, H.-U. Esslinger, and H. D. Yannicelli The Effects of Multiple Doses of Fenofibrate on the Pharmacokinetics of Pravastatin and Its 3{alpha}-Hydroxy Isomeric Metabolite J. Clin. Pharmacol., August 1, 2005; 45(8): 947 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Alayli, K. Cengiz, F. Canturk, D. Durmus, Y. Akyol, and E. B Menekse Acute Myopathy in a Patient with Concomitant Use of Pravastatin and Colchicine Ann. Pharmacother., July 1, 2005; 39(7): 1358 - 1361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Morera, G. Gervasini, J. A Carrillo, and J. Benitez Using a Computerized Drug Prescription Screening System to Trace Drug Interactions in an Outpatient Setting Ann. Pharmacother., July 1, 2004; 38(7): 1301 - 1306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Treiber, R. Schneiter, S. Delahaye, and M. Clozel Inhibition of Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake Is the Major Determinant in the Pharmacokinetic Interaction between Bosentan and Cyclosporin A in the Rat J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 1121 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Jacobsen, U. Christians, and L. Z. Benet In Vitro Evaluation of the Disposition of A Novel Cysteine Protease Inhibitor Drug Metab. Dispos., November 1, 2000; 28(11): 1343 - 1351. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. J. Herman Drug interactions and the statins Can. Med. Assoc. J., November 1, 1999; 161(10): 1281 - 1286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Jacobsen, G. Kirchner, K. Hallensleben, L. Mancinelli, M. Deters, I. Hackbarth, K. Baner, L. Z. Benet, K.-F. Sewing, and U. Christians Small Intestinal Metabolism of the 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitor Lovastatin and Comparison with Pravastatin J. Pharmacol. Exp. Ther., October 1, 1999; 291(1): 131 - 139. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
