Different inhibition and induction profiles of hepatic drug metabolism in rats and dogs by two structurally related pyridyl diazinone cardiotonic agents.
ICI 153,110 and ICI 170,777, two pyridyl diazinone cardiotonic agents, produced a different profile of effects on hepatic microsomal mixed function oxidase enzymes following multiple oral dosing to rats and dogs; these differences may be related to the molecular dimensions of the two molecules. ICI 153,110 significantly increased levels of total P450, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase in rat microsomes, indicating an induction profile (P448) similar to that of beta-naphthoflavone. This was supported by gel electrophoresis (SDS-PAGE) of microsomal proteins; a similar type of induction was observed in dog microsomes. In contrast, ICI 170,777 produced no changes indicating enzyme induction in either rat or dog. Instead, ICI 170,777 appeared to inhibit specifically the activity of aldrin epoxidase in the rat. Inhibitory activity was also indicated in the rat by prolongation of pentobarbitone sleeping time following single oral doses of either ICI 153,110 or ICI 170,777. The time-course of this effect appeared to correlate more closely with the profile of circulating metabolites, although both parent compounds were found to produce type II spectral changes on interaction with control rat microsomes. The molecular dimensions (area/depth2) of the compounds supported the finding that only ICI 153,110 should interact with or induce P448 isozymes.
McKillop
D
D
Safety of Medicines Department, ICI Pharmaceuticals, Macclesfield, Cheshire, U.K.
Pickup
K J
KJ
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004095:Dihydropyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D006207:Half-Life; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011724:Pyridazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013829:Thiadiazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D002316:Cardiotonic Agents; D004095:Dihydropyridines; D011724:Pyridazines; D011725:Pyridines; D013829:Thiadiazines; D014665:Vasodilator Agents; C060733:ICI 170777; C064747:ICI 153110; D006899:Mixed Function Oxygenases