Factors Affecting the Metabolism of Phenacetin I. Influence of Dose, Chronic Dosage, Route of Administration and Species on the Metabolism of [1-¹⁴C-Acetyl]Phenacetin

Abstract

1. Metabolism and excretion of [acetyl-1-¹⁴C]phenacetin have been studied in relation to dose, chronic dosage, route of administration and species.

2. The drug is largely metabolized in the rat, rabbit, guinea-pig, ferret and man by oxidative de-ethylation and deacetylation as well as by minor pathways of aromatic hydroxylation and cysteine conjugation.

3. Species differences exist in the extent to which the various reactions occur; deacetylation is highest in the rat and ferret (21 and 13% of dose respectively); aromatic hydroxylation of phenacetin to 2-hydroxyphenacetin is highest in the ferret (6% of dose) but low (0·1%) in the other species; the formation of the 3-cysteine conjugate of N-acetyl-p-aminophenol is highest in the rabbit (8%) and least in the guinea-pig (0·3%); the pattern of conjugation of N-acetyl-p-aminophenol varies with species, glucuronide conjugation being dominant in the rabbit, guinea-pig and ferret, whereas sulphate conjugation is the main pathway in the rat.

4. The pattern of elimination in the rat of a large oral dose (2000 mg/kg) of [acetyl-¹⁴C]phenacetin differs from that of a smaller dose (125 mg/kg), with (a) slower overall excretion at the higher dose (b) a marked relative increase in the proportion of the drug undergoing deacetylation and (c) a change in the pattern of conjugation of the N-acetyl-p-aminophenol at the higher dose in favour of glucuronic acid conjugation.

5. The pattern of excretion of [acetyl-¹⁴C]phenacetin in the rat is the same when the drug is given orally or by intraperitoneal injection. However, the elimination of radioactivity is slower in rats treated chronically for 14 days with the drug.

6. The findings are discussed in relation to some of the biological properties of phenacetin.