Efficacy, tissue distribution and biliary excretion of methyl (3R*,5S*)-(E)-3,5-dihydroxy-9,9-diphenyl-6,8-nonadienoate (CP-83101), a hepatoselective inhibitor of HMG-CoA reductase activity in the rat.
Methyl (3R*,5S*)-(E)-3,5-dihydroxy-9,9-diphenyl-6,8-nonadienoate, CP-83101, was identified as a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, inhibiting enzyme activity in vitro with an IC50 of 8.5 +/- 0.7 microM and a Ki with respect to HMG-CoA of 2.6 microM. CP-83101 also inhibited rat hepatic sterol biosynthesis by 39 +/- 7% at a dose of 100 mg/kg. [3H]CP-83101, administered orally to rats, exhibited peak plasma levels at approximately 1 hr that declined thereafter with an apparent half-time of 2-3 hr. Peak tissue levels also occurred 1 hr following oral administration of [3H]CP-83101. The decline in radioactivity in the liver, however, was considerably slower than that noted in blood, whereas the half-life in non-hepatic tissues was approximately 1 hr. Liver/blood ratios of 14, and liver/lens ratios of greater than 3000, following oral administration of [3H]CP-83101, were similar to those previously reported for other HMG-CoA reductase inhibitors, suggesting a high degree of tissue selectivity. In addition, liver/adrenal and liver/ovary ratios were approximately 1000 at all time points examined between 30 min and 24 hr following oral [3H]CP-83101 administration, indicating a high specificity for hepatic versus other steroidogenic tissues. Evaluation of intravenous versus oral administration of the water-soluble, free acid, sodium salt of [3H]CP-83101 in bile duct canulated rats indicated that approximately 20% of orally administered CP-83101 is absorbed from the gastrointestinal tract, and that absorbed CP-83101 is cleared rapidly from the plasma via the liver and from the liver via the bile. In addition, several lines of evidence suggest that CP-83101 may undergo enterohepatic recirculation. Agents of this synthetic series may thus possess advantages over other HMG-CoA reductase inhibitors with respect to tissue kinetics and specificity.
Department of Metabolic Diseases, Pfizer Inc., Groton, CT 06340.
H J
HJ
Harwood
M
M
Silva
C E
CE
Chandler
L
L
Mikolay
L D
LD
Pellarin
E
E
Barbacci-Tobin
L T
LT
Wint
P A
PA
McCarthy
D000284:Administration, Oral; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D014018:Tissue Distribution
D005231:Fatty Acids, Unsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C065763:3,5-dihydroxy-9,9-diphenyl-6,8-nonadienoate; D002784:Cholesterol