Biopharmaceutical study of pyrithioxin following oral and intravenous administration to dog.

Abstract

After single oral and intravenous administration of pyrithioxin (I) to beagle dogs, the blood levels of 5'-desoxy-5'-methylsulfinylpyridoxol (II), one of the main metabolites of I in blood and urine, were measured with a high-performance liquid chromatography. The existence of I was not detected in blood samples for 24 hr after an oral administration of I at dose levels less than 100 mg of I/kg. But, it was detected in the first blood sample collected 1 min after intravenous injection at dose levels of 10 and 5 mg/kg, but not in the sample collected 3 min after injection. After oral and intravenous administrations of I, non-first-order disappearance of II in blood was observed. The results suggest a possible enterohepatic cycling of I-glucuronide (I-G). A study was made on the metabolites in the urine samples after two routes of administration, demonstrating the existence of I-G, II, and II-glucuronide (II-G). Likewise, II and II-G were found in the urine following oral and intravenous administrations of II·HCl. A total amount of II in mole percent of dose excreted in the urine after oral administration of I·2HCl filled in hard gelatin capsules decreased significantly with an increase of dose suggesting change of bioavailability with change of the dose. The results were seemed to be partially subjected to the poor absorbability at the intestinal tract owing to the low solubility of I at the physiological pH of 4-7.5. Mucosal-to-serosal permeation of I across the everted rat intestine in vitro was found to proceed without metabolism during and after permeation. Thus, it may be considered that the metabolism of I takes place after absorption, mainly in the liver.