Biliary and renal excretion,hepatic metabolism,and hepatic subcellular distribution of metronidazole in the rat

We studied the biliary and renal excretion, hepatic metabolism, and hepatic subcellular distribution of [¹⁴C]metronidazole in bile fistula rats. An average of 71.1 per cent of an intraduodenal or intravenous dose of [¹⁴C]metronidazole was excreted in 24 hr, 23.9 per cent in bile and 47.6 per cent in urine. Renal pedicle ligation caused a 150 per cent increase in biliary excretion of label, whereas phenobarbital pretreatment had no effect. The majority of label in bile and urine was associated with a polar derivative, tentatively identified by thin-layer chromatography and enzymatic hydrolysis as the monoglucuronide conjugate of metronidazole. After intraduodenal administration of purified conjugated [¹⁴C]metronidazole to rats with ligated renal pedicles, only a small amount of label (12.6 per cent of dose in 24 hr) appeared in bile. Growth inhibition studies showed the glucuronide conjugate to be devoid of antimicrobial activity against a metronidazole-sensitive organism, Tritrichomonas foetus. Uptake studies indicated that these organisms were incapable of concentrating conjugated metronidazole. Fractionation of rat liver homogenates by differential centrifugation after intravenous [¹⁴C]metronidazole showed that 90 per cent of label present in liver was in the non-particulate fraction. Our results in rats indicate that metronidazole undergoes an enterohepatic circulation and that the liver plays a major role in the metabolism and excretion of this compound.