From in vivo disposition to therapeutic action: Tracing the pharmacokinetic journey and unveiling the anti-UC potential of oridonin and its sulfonate-conjugate.

Oridonin, a bioactive ingredient from Rabdosiae rubescentis (Hemsl.) Hara, exhibits potent anti-inflammatory properties in the treatment of ulcerative colitis. However, its low bioavailability poses challenges in fully elucidating its therapeutic effect. To comprehensively understand how oridonin works, a systematic investigation was conducted to evaluate the pharmacokinetics of oridonin and its major metabolites in rats using UPLC-MS/MS. Additionally, their pharmacological effects and mechanisms on DSS-elicited ulcerative colitis were evaluated. The sulfonated metabolites of oridonin were identified in rats for the first time, primarily due to the presence of an α, β-unsaturated carbonyl group which was susceptible to sulfonation. This deduction was supported by comparing the bioavailability of oridonin (F = 5.65 %) and dihydro-oridonin (F = 40.80 %) which lacks this moiety. Interestingly, the sulfonated metabolites exhibited a dramatically higher exposure compared to oridonin, as confirmed by excretion and tissue distribution studies. The sulfonates were mainly localized in the colon with a concentration approximately 4000 times higher than that of oridonin, and 61.48 % were excreted via feces. Moreover, both oridonin and its sulfonate-conjugate significantly alleviated disease severity in ulcerative colitis. This was achieved through modulating oxidative stress, rebalancing pro- and anti-inflammatory factors at the mRNA level, and upregulating tight junction proteins in the colon. Transcriptomics analysis further demonstrated that oridonin and its sulfonate-conjugate exerted anti-ulcerative colitis effects by regulating the PI3K/AKT signaling pathway. These results not only clarify the pharmacological substances and mechanism of action of oridonin but also identify its sulfonate-conjugate as a promising candidate for treating inflammatory bowel disease.