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Enhanced drug metabolism and renal dysfunction.

In a recent paper Aitio & Vuorenmaa (1980) reported that six of their sixty-four patients receiving long term oral therapy with disopyramide, a novel antiarrhythmic drug, had unexpectedly high plasma levels of mono-N-dealkyldisopyramide, the major metabolite of disopyramide, while the parent drug's level was ineffectively low. Three of these six patients were taking simultaneously phenytoin, a well-known inducer of the hepatic drug-metabolizing enzymes. The other three were not given regularly any enzyme inducing drugs and had impaired renal function. One of the patients receiving phenytoin combined with disopyramide also had mild renal dysfunction. Discrepancy between the high dose of disopyramide and its low plasma level with concomitant increase in the metabolite concentration and diminution in clinical efficacy was apparent in all four patients with impaired renal function. The likely enhancement of the metabolic rate of disopyramide in patients given phenytoin was assumed to be due to enzyme induction, but a definitive explanation for the saffie phenomenon in patients with renal dysfunction was not made. Increased drug metabolism due to enzyme induction might also be a mechanism underlying the above findings in patients with impaired renal function, since the plasma antipyrine half-life, an index of the drug metabolizing capacity of the liver (Vessell & Page, 1968), is diminished in chronic renal failure (Maddocks, Wake & Harber, 1975). In favour of this assumption further evidence was obtained in our recent studies performed in children with mild renal dysfunction. All of our patients had definite clinical symptoms of renal disease, but none of them was in a uraemic or pre-uraemic state. The rate of disappearance of antipyrine from saliva, which is known to be the same as that from plasma (Vessel, Passananti, Glenwright & Dvorchik, 1975), was studied in eighteen children without renal disease and in fourteen children with impaired renal function. Plasma creatinine concentrations varied between 1 and 1.5 mg/lOO ml (88 and 132 ,umol/l) in eleven patients and exceeded 1.5 mg/100 ml (132 ,umol/l) only in the other three patients. Antipyrine was given in an oral dose of 18 mg/kg. Saliva was collected 3, 6, 9, 12 and 24 h after ingestion. The half-lives were calculated from the salivary disappearance curves, the antipyrine concentrations being determined by the procedure of Brodie, Axelrod, Soberman & Levy (1949). The mean + s.e. mean antipyrine half-life was significantly (P<O.001) shorter in patients with renal dysfunction (3.0 ± 0.4 h) than in children with no renal disease (7.9 ± 0.7 h). The urinary excretion of D-glucaric acid, another index of the hepatic drug-metabolizing enzyme capacity (Hunter, Maxwell, Corrella, Stewart& Williams, 1971), was studied in thirty-five children without renal impairment and in fifty children with mild renal dysfunction. Plasma creatinine concentrations in the kidney patients ranged from 0.8 to 1.6 mg/100 ml (70 to 141 umol/l). Seventeen patients and twelve control subjects received treatment with a known enzyme inducer (indomethacin, steriods, tranquillizers). A 24-h urine specimen was collected and the concentration of D-glucaric acid was determined by the method of Marsh (1963) as modified by Simmons, Davis, Dordoni & Williams (1974). The individual values measured are shown in Figure 1. The mean + s.e. mean D-glucaric acid excretion (,umol/g creatinine) was 29.1 + 4.0 in