Hepatic microsomal induction profile of carbamic acid [[2,6-bis(1- methylethyl)phenoxy] sulfonyl]-2,6-bis(1-methylethyl) phenyl ester, monosodium salt (PD138142-15), a novel lipid regulating agent.
Induction of hepatic microsomal cytochrome P450 produced by carbamic acid [2,6-bis(1-methylethyl)phenoxy]sulfonyl]-2,6-bis(1-methylethyl) phenyl ester, monosodium salt (PD138142-15), a novel water-soluble inhibitor of acyl-CoA: cholesterol acyltransferase, was examined in male and female rats, dogs, and monkeys, and in male guinea pigs. Relative to control, PD138142-15 increased hepatic microsomal total spectral P450 in all species examined. Hepatic microsomal ethoxyresorufin-O-deethylase, pentoxyresorufin-O-dealkylase, and peroxisomal carnitine acetyltransferase activities and cyanide-insensitive Beta-oxidation were affected only marginally. Erythromycin-N-demethylase activity was increased (2- to 6-fold) in all three species in which it was examined (rat, dog and pig). Marked increases in immunoreactive P450 3A were noted in the rats and dogs, while slight increases were seen in monkeys. Pharmacokinetic studies of PD138142-15 in rats and dogs revealed pronounced decreases (80-90%) in plasma Cmax and AUC within 2 weeks of initiation of daily dosing. In spite of the marked decline in plasma drug levels, efficacy in dogs, as determined by serum cholesterol levels, was maintained for up to 6 weeks with continued dosing. Potential acid (gastric) breakdown products of PD 138142-15 were examined for their hepatic cytochrome P450 induction profiles in rats adn were found to differ both quantitatively and qualitatively from profiles produced by the parent compound. This suggested that induction observed in rats was due to parent PD138142-15 and not to any of the known potential acid breakdown products. The cumulative data establish that PD 138142-15 is an inducer of P450 3A in rats and dogs. The results also suggest that P450 3A is induced in monkeys and pigs as well, although the data are less definitive. Decreases in plasma drug levels imply that the compound may be an autoinducer in dogs and rats. The maintenance of efficacy in spite of decreased drugs levels in dogs suggests that the effects on serum cholesterol are due to a metabolite or that cholesterol lowering effects occur before the compound is metabolized by the liver.
Robertson
D G
DG
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Ann Arbor, MI 48106-1047.
Krause
B R
BR
Welty
D F
DF
Wolfgang
G H
GH
Graziano
M J
MJ
Pilcher
G D
GD
Urda
E
E
D000818:Animals; D002219:Carbamates / Q000493:pharmacokinetics / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004285:Dogs; D004790:Enzyme Induction; D005260:Female; D006168:Guinea Pigs; D000960:Hypolipidemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D013045:Species Specificity; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors
D002219:Carbamates; D000960:Hypolipidemic Agents; C086204:((2,6-bis(1-methylethyl)phenoxy)sulfonyl)carbamic acid 2,6-bis(1-methylethyl)phenyl ester; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D002785:Sterol O-Acyltransferase