Klammers, Florian published the artcileEstimation of fraction metabolized by cytochrome P450 enzymes using long-term cocultured human hepatocytes, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is itraconazole antiinflammatory CYP450 enzyme hepatic metabolism.
Estimation of the fraction of a drug metabolized by individual hepatic CYP enzymes relative to hepatic metabolism (fm,CYP) or total clearance h as been challenging for low turnover compounds due to insufficient resolution of the intrinsic clearance (CLint) measurement in vitro and difficulties in quantifying the formation of low abundance metabolites. To overcome this gap, inhibition of drug depletion or selective metabolite formation for 7 marker CYP substrates was investigated using chem. inhibitors and a micro-patterned hepatocyte coculture system (HepatoPac). The use of 3μM itraconazole was successfully validated for estimation of fm,CYP3A4 by demonstration of fm values within a 2-fold of in vivo estimates for 10 out of 13 CYP3A4 substrates in a reference set of marketed drugs. Other CYP3A4 inhibitors (ketoconazole and posaconazole) were not optimal for estimation of fm,CYP3A4 for low turnover compounds due to their high CLint. The current study also demonstrated that selective inhibition sufficient for fm calculation was achieved by inhibitors of CYP1A2 (20μM furafylline), CYP2C8 (40μM montelukast), CYP2C9 (40μM sulfaphenazole), CYP2C19 [3μM (-)N-3-benzyl-phenobarbital], and CYP2D6 (5μM quinidine). Good estimation of fm,CYP2B6 was not possible in this study due to the poor selectivity of the tested inhibitor (20μM ticlopidine). The approach verified in this study can result in an improved fm estimation that is aligned with the regulatory agencies’ guidance and can support a victim drug-drug interaction risk assessment strategy for low clearance discovery and development drug candidates.
Drug Metabolism & Disposition published new progress about Cytochrome P450 CYP2B6 inhibitors. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.
Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem