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The effects of physicochemical properties of pethidine and its basic metabolites on their buccal absorption and renal elimination

The pKa values, RF values, partition coefficients between n‐heptane and phosphate buffer (pH = 7·4), and buccal absorption tests of pethidine and its basic metabolites, norpethidine and pethidine N‐oxide, have been determined. The amounts of these compounds recovered in the 48 h urine samples after intramuscular administration of pethidine (1·5 mg kg−1) to six healthy subjects varies with urinary pH values: the recovery from acidic urine (pH 5·0) is 15·2 to 52·0%, 6·7 to 12·9% and 0·2 to 2·3% of dose for pethidine, norpethidine and pethidine N‐oxide respectively; in alkaline urine (pH 8·0) the values are 0·8 to 1·8%, 0·6 to 2·8% and 0·3 to 2·1% respectively. The physicochemical properties (pKa values, RF values, partition coefficients) and buccal absorption of pethidine, norpethidine and pethidine N‐oxide are in good agreement with the pattern of their renal elimination in acidic and alkaline urine conditions. The contribution of the physicochemical properties of pethidine and its metabolites to the drug's disposition in the body and the effect of urinary pH on its metabolism should be taken into account in pharmacokinetic studies and interpretation of intersubject variation in response to pethidine.