This study investigated the pharmacokinetics of tofacitinib in rats and the effects of first-pass\nmetabolism on tofacitinib pharmacokinetics. Intravenous administration of 5, 10, 20, and 50 mg/kg\ntofacitinib showed that the dose-normalized area under the plasma concentration-time curve from\ntime zero to infinity (AUC) was significantly higher at 50 mg/kg than at lower doses, a difference\npossibly due to saturation of the hepatic metabolism of tofacitinib. Oral administration of 10, 20, 50,\nand 100 mg/kg tofacitinib showed that the dose-normalized AUC was significantly higher at 100\nmg/kg than at lower doses, a difference possibly due to saturation of the intestinal metabolism of\ntofacitinib. Following oral administration of 10 mg/kg tofacitinib, the unabsorbed fraction from the rat\nintestine was 3.16% and the bioavailability (F) was 29.1%. The AUC was significantly lower (49.3%)\nafter intraduodenal, compared to intraportal, administration, but did not differ between intragastric\nand intraduodenal administration, suggesting that approximately 46.1% of orally administered\ntofacitinib was metabolized through an intestinal first-pass effect. The AUC was also significantly\nlower (42%) after intraportal, compared to intravenous, administration, suggesting that the hepatic\nfirst-pass effect on tofacitinib after entering the portal vein was approximately 21.3% of the oral\ndose. Taken together, these findings suggest that the low F of tofacitinib is due primarily to intestinal\nfirst-pass metabolism.
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