Small intestinal metabolism of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and comparison with pravastatin.
We compared the intestinal metabolism of the structurally related 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors lovastatin and pravastatin in vitro. Human small intestinal microsomes metabolized lovastatin to its major metabolites 6'beta-hydroxy (apparent K(m) = 11.2 +/- 3.3 microM) and 6'-exomethylene (apparent K(m) = 22.7 +/- 9.0 microM) lovastatin. The apparent K(m) values were similar for lovastatin metabolism by human liver microsomes. 6'beta-Hydroxylovastatin formation by pig small intestinal microsomes was inhibited with the following inhibition K(i) values: cyclosporine, 3.3 +/- 1.2 microM; ketoconazole, 0.4 +/- 0.1 microM; and troleandomycin, 0.8 +/- 0.9 microM. K(i) values for 6'-exomethylene lovastatin were similar. Incubation of pravastatin with human small intestinal microsomes resulted in the generation of 3'alpha,5'beta, 6'beta-trihydroxypravastatin (apparent K(m) = 4560 +/- 1410 microM) and hydroxypravastatin (apparent K(m) = 5290 +/- 1740 microM). In addition, as in the liver, pravastatin was metabolized in the small intestine by sulfation and subsequent degradation to its main metabolite 3'alpha-iso-pravastatin. It was concluded that lovastatin is metabolized by cytochrome P-450 3A enzymes in the small intestine. Compared with lovastatin, the cytochrome P-450-dependent intestinal intrinsic clearance of pravastatin was >5000-fold lower and cannot be expected to significantly affect its oral bioavailability or to be a significant site of drug interactions.
Jacobsen
W
W
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California, USA.
Kirchner
G
G
Hallensleben
K
K
Mancinelli
L
L
Deters
M
M
Hackbarth
I
I
Baner
K
K
Benet
L Z
LZ
Sewing
K F
KF
Christians
U
U
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D016572:Cyclosporine / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology; D008148:Lovastatin / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D017035:Pravastatin / Q000378:metabolism*; D013552:Swine; D014217:Troleandomycin / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D008148:Lovastatin; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017035:Pravastatin; D007654:Ketoconazole