Additional routes in the metabolism of phenacetin.
omega-Hydroxylation of the ethyl moiety of phenacetin by rabbit-liver microsomal preparations was slow, but was increased 10-fold by pretreatment of the animals with phenobarbitone (PB), and was decreased 2.8-fold by treatment with 3-methylcholanthrene (3-MC) or beta-naphthoflavone (beta-NF). N-[4-(2-hydroxyethoxy)phenyl]acetamide (beta-HAP), the omega-hydroxylation product, which was detected in trace amounts only in the urine of rabbits injected with phenacetin, was converted into [4-(acetylamino)phenoxy]acetic acid (4-APA) by the microsomal and cytosolic fraction of liver homogenate and NADP+ or NAD+. Rabbits excreted 56% of a dose of beta-HAP as 4-APA in the 48 h urine. Phenacetin, injected i.p. into rabbits previously treated with PB, was excreted in the urine as 4-APA (12.2% of dose). beta-HAP formed endogenously or added as substrate in vitro was recovered as the O-acetyl derivative, when ethyl acetate was used for extraction of metabolites from microsomal incubation mixtures. (omega-1)-Hydroxylation of the ethyl moiety of phenacetin, which gave 4-acetamido-phenol, occurred rapidly with rabbit-liver microsomal preparations, and was not increased significantly after pretreatment of animals with either PB or 3-MC. omega-Hydroxylation of the acetic moiety of phenacetin by rabbit-liver preparations to give N-(4-ethoxyphenyl)glycolamide (4-GAP) was slow, but was increased three-fold after pretreatment of animals with 3-MC or beta-NF, whereas PB had no effect. 4-GAP was detected in trace amounts only in the urine of rabbits injected i.p. with phenacetin. N-Hydroxylation of phenacetin by rabbit-liver microsomal preparations was slow, but increased three-fold after treatment of animals with 3-MC, and was unchanged by PB. N-Hydroxylation of phenacetin by hepatic microsomes from 3-MC-treated rabbits was 26 times slower than that of 2-acetylaminofluorene; no N-hydroxy derivatives of N-(4-chlorophenyl)acetamide and propanil were detected in vitro.
D000107:Acetylation; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D002855:Chromatography, Thin Layer; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006900:Hydroxylation; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010615:Phenacetin / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D010615:Phenacetin; D010634:Phenobarbital