Metabolism and biliary excretion of phenanthridinium salts—I: Nature of the biliary metabolite

Abstract

The nature of the biliary metabolites of three phenanthridinium salts—3,8-diamino-6- p-aminophenyl-5-methylphenanthridinium chlori (150C47), 3,8-diamino-6-phenyl-5-ethylphenanthridinium bromide (ethidium), and 2-amino-6- p-carbethoxyaminophenyl-5-methylphenanthridinium sulfate (carbidium) —has been investigated in rats with ligated renal pedicles. Up to 50 per cent of a small intravenous dose of each of these compounds may be excreted in the bile of rats with ligated renal pedicles in 1 hr depending on the dose and individual variation. At the dose selected, about 15 per cent of the dose was excreted in the first hour after injection. Sixty-five percent of a 15 mg/kg dose of 150C47 was recovered in the bile in 11–21 hr; 85 percent of this total was excreted within 5 hr. Of the material recovered, approximately 15 per cent was unchanged 150C47. The major metabolite present in bile was a monoacetyl amino conjugate and this accounted for about 50 per cent of the material recovered. Two other metabolites were also shown to be present and these are also believed to be acetyl conjugates. One of these is probably a diacetylated compound and accounted for about 25 per cent of the material recovered. The other accounted for the remaining 10 per cent. During the first hour after injection, the material was almost entirely in the form of the major metabolite plus the unchanged compound. After injection of the major monoacetyl metabolite, only the injected monoacetyl compound and the diacetylated one could be detected in bile, and the rate of excretion exceeded the rate of excretion of all forms of 150C47 in control rats given the same dose of 150C47. Of a 15 mg/kg dose of ethidium, 50–55 per cent was recovered in the bile in 16–18 hr. Unchanged ethidium accounted for 20–25 per cent of the material present. Two metabolites were found and these are both believed to be monoacetyl amino conjugates. They accounted for 65–70 per cent and 10 per cent of the material recovered; 85–90 per cent of this total was excreted within 5 hr. Carbidium is excreted in bile as the unchanged compound and its acetyl conjugate. Only one acetyl conjugate is possible for this compound and it was the only metabolite found in bile. Of a dose of 15 mg/kg, 60–65 per cent was recovered in 10–16 hr. About 20 per cent of the material recovered was unchanged carbidium; the remaining 80 per cent was the acetyl derivative. During the first hour after injection, 55 per cent of the material excreted was unchanged carbidium.