Indoxyl sulfate, a uremic toxin, is biotransformed from indoxyl-beta-D-glucoside (indican) in rats.

Indican (Indoxyl-beta-D-glucoside) is present in many Chinese herbs such as Isatis indigotica, Clerodendrum crytophyllum, Glehnia littoralis, Polygonum tinctorium and P. perfoliatum. This study aims to investigate whether indoxyl sulfate, a uremic toxin, would be biotransformed from indican in rats. Indican was administered intravenously and orally to Sprague-Dawley rats. The blood samples were withdrawn via cardiopuncture at specific time points and the serum concentrations of indican and indoxyl sulfate were assayed by HPLC method. The results showed that indican was rapidly and extensively metabolized to indoxyl sulfate either given intravenously or orally. Indoxyl sulfate showed markedly higher systemic exposure than indican. Because indoxyl sulfate is a harmful uremic toxin, we suggest that the content of indican in the aforementioned medicinal plants be quantitated and well controlled to ensure the safety for clinical use.

Transporter-mediated interaction of indican and methotrexate in rats.

Indican (indoxyl-ß-D-glucoside) is present in several Chinese herbs e.g. Isatis indigotica, Polygonum tinctorium and Polygonum perfoliatum. The major metabolite of indican was indoxyl sulfate (IS), an uremic toxin which was a known substrate/inhibitor of organic anion transporter (OAT) 1, OAT 3 and multidrug resistance-associated protein (MRP) 4. Methotrexate (MTX), an important immunosuppressant with narrow therapeutic window, is a substrate of OAT 1, 2, 3, 4 and MRP 1, 2, 3, 4. We hypothesized that IS, the major metabolite of oral indican, might inhibit the renal excretion of MTX mediated by OAT 1, OAT 3 and MRP 4. Therefore, this study investigated the effect of oral indican on the pharmacokinetics of MTX. Rats were orally given MTX with and without indican (20.0 and 40.0 mg/kg) in a parallel design. The serum MTX concentration was determined by a fluorescence polarization immunoassay. For mechanism clarification, phenolsulfonphthalein (PSP, 5.0 mg/kg), a probe substrate of OAT 1, OAT 3, MRP 2 and MRP 4, was intravenously given to rats with and without a intravenous bolus of IS (10.0 mg/kg) to measure the effect of IS on the elimination of PSP. The results indicated that 20.0 and 40.0 mg/kg of oral indican significantly increased the area under concentration-time curve0-t (AUC0-t) of MTX by 231% and 259%, prolonged the mean residence time (MRT) by 223% and 204%, respectively. Furthermore, intravenous IS significantly increased the AUC0-t of PSP by 204% and decreased the Cl by 68%. In conclusion, oral indican increased the systemic exposure and MRT of MTX through inhibition on multiple anion transporters including OAT 1, OAT 3 and MRP 4 by the major metabolite IS.