Effect of Sophora flavescens on the pharmacokinetics of carbamazepine in rats

Abstract

Carbamazepine (CBZ), an antiepileptic with narrow therapeutic window, is a substrate of CYP 3A4 which metabolizes CBZ to carbamazepine-10,11-epoxide (CBZE). CBZE is an active and toxicity metabolite, and it is a substrate of MRP-2. Using CBZ for a long time can cause hepatic injury. Sophora flavescens (SF) is a medicinal herb used for the protected hepatic injury. This study investigated the acute and chronic effects of SF on the pharmacokinetics of CBZ in rats. The concentrations of CBZ and CBZE in plasma and tissues were determined by HPLC method. The results showed that SF which significantly decreased the AUC0-t of CBZ, increased CBZE conversely. Tissue analysis showed that the concentrations of CBZ and CBZE in brain and liver were decreased by SF. In addition, the distribution of CBZE in kidney was reduced significantly, which influenced the CBZE excretion and increased the drug toxic potentially. Results in the current study suggest that patients using CBZ might be cautioned in the use of SF extract or Sophora-derived products. Meanwhile, patients receiving drugs which are substrates of CYP 3A4 and/or MRP-2 should be advised of the potential herb-drug interaction to reduce the risk of therapeutic failure or increased toxicity of conventional drug therapy.

Drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to lamotrigine differs from that due to other drugs

“…3,7 Hepatic failure, including elevation of serum transaminases, is a common finding. Whereas LTG is mainly metabolized by uridine 5 0 -diphospho-glucuronosyltransferase (UGT), carbamazepine is metabolized to the toxic metabolite carbamazepine-10, 11-epoxide, by the enzyme CYP3A4, 26 while phenytoin is mainly metabolized to 4 0 -hydroxylated phenytoin by CYP2C9, and to a minor extent by CYP2C19. The reason for this difference in DIHS/DRESS due to LTG versus other drugs, including anticonvulsants such as carbamazepine and phenytoin, remains unclear.…”

“…Carbamazepine and phenytoin are typical cytochrome P450 (CYP) substrates. Whereas LTG is mainly metabolized by uridine 5 0 -diphospho-glucuronosyltransferase (UGT), carbamazepine is metabolized to the toxic metabolite carbamazepine-10, 11-epoxide, by the enzyme CYP3A4, 26 while phenytoin is mainly metabolized to 4 0 -hydroxylated phenytoin by CYP2C9, and to a minor extent by CYP2C19. 27 Generally, unstable reactive metabolites metabolically activated by CYP enzymes induce hepatotoxicity.…”

Carbamazepine Shows Plasma and Tissue Pharmacokinetic Interactions with Ajuga bracteosa Extract in Rats

“…To date, the pharmacokinetic HDIs for CBZ, have been studied with polygonum cuspidatum, a resveratrol rich nutraceutical, ferulic acid, sophora flavescens and traditional beverages, including tamarind, mango, sugarcane, and red bull [23][24][25][26]. HDIs occur primarily during the process of absorption, distribution, metabolism, and clearance of drugs.…”

“…Ursolic acid potently inhibits CYP2C19 iso-enzyme and plays an important role in HDIs by altering the pharmacokinetics of the co-administered drugs [34,35], stigmasterol powerfully inhibits MDR1-P-gp and CYP3A4, CYP3A5, and CYP19 [36,37] and the sitosterol inhibits CYP3A4 and CYP2D6 [38]. The CYP3A4, CYP2C8, and CYP1A2 play vital role in CBZ metabolism [25,39,40]. Pharmacokinetics data indicate the significant effect of strong inhibitors of CYP isoenzymes in plant extracts on the pharmacokinetics of the drug.…”