Metronidazole and antipyrine metabolism in the rat: Clearance determination from one saliva sample

Abstract

1. The applicability of a simple, non-invasive method for assessment of metronidazole and antipyrine metabolism in rats in vivo was investigated.

2. In 48 sample pairs of blood and pilocarpine-stimulated saliva from six rats the concentration of metronidazole was almost identical (r = 0.97)

3. In 26 rats the clearance could be determined from one sample without loss of precision and accuracy compared with conventional determinations (r=0.99). If urine was collected for 24 h the fractional clearance representing each elimination pathway could be determined.

4. Pretreatment with phenobarbitone increased the fractional clearance of metronidazole by oxidation and glucuronidation 3.8-fold and 1.6-fold, respectively, whereas 3-methylcholanthrene pretreatment increased the rate of oxidation 10-fold and decreased the rate of glucuronidation 0.5fold.

5. The clearance and fractional clearances of metronidazole and antipyrine administered in a mixture could be determined from the same saliva sample and urine collected for 24 h without drug-drug interactions.

6. Phenobarbitone pretreatment increased the formation rate of all metabolites of metronidazole and antipyrine administered in a mixture, whereas β-naphthoflavone increased the formation rates of only the oxidative metronidazole metabolites, norantipyrine and 4-hydroxyantipyrine, but not metronidazole glucuronide or 3-hydroxymethylantipyrine.

7. A mixture of metronidazole and antipyrine and non-invasive sampling are recommendable for the study of the differential metabolism of foreign compounds in rats in vivo.