Isopropylbiphenyl metabolism in the rat. Relationships between metabolism, pharmacology and toxicology.

Abstract

1. 4-Iso[14C]propylbiphenyl was well absorbed following either oral or intraperitoneal administration. Excretion of 14C into faeces was greater than excretion into urine. At 48 h after dosing, appreciable amounts of 14C remained in the rat carcass. 14C was found in tissues examined at 48 h, but was unusually high only in fat.2. Rats with biliary cannulae excreted about half of an oral dose in bile in 48 h.3. The principal metabolite in plasma was biphenylpropionic acid, with small amounts of biphenyl-2-propanol and biphenyl-α-methyl glycolic acid. Unchanged isopropylbiphenyl was also present.4. Metabolites in urine and bile were mainly ring-hydroxylated forms of the plasma metabolites, principally hydroxybiphenylpropionic acid and hydroxybiphenyl-2-propanol. The amount of hydroxybiphenyl-α-methylglycolic acid was unexpectedly small. All phenolic metabolites occurred as conjugates.5. Biphenylpropionic acid is probably the metabolite mainly responsible for the anti-inflammatory action of isopropylbiphenyl, being formed via biphenyl-1-propanol, a metabolite not found in these studies. This alcohol, when administered to rats, was readily converted to the acid, and was a potent antiinflammatory agent.6. Biphenyl-α-methylglycolic acid is formed via the tertiary alcohol, biphenyl-2-propanol, and is probably important in the renal toxicity of isopropylbiphenyl. An unknown salt of biphenyl-α-methylglycolic acid was a major component of renal calculi.7. Incubation of isopropylbiphenyl with rat liver 15 000 g supernatant yielded biphenyl-2-propanol and biphenylpropionic acid. The primary alcohol biphenyl-1-propanol was not isolated. Liver enzyme preparations from phenobarbital-treated rats yielded the tertiary carbinol, biphenylpropionic acid, the primary carbinol and minor amounts of ring-hydroxylated isopropylbiphenyl.