153212-75-0Relevant articles and documents
Engineering Macaca fascicularis cytochrome P450 2C20 to reduce animal testing for new drugs
Rua, Francesco,Sadeghi, Sheila J.,Castrignanò, Silvia,Di Nardo, Giovanna,Gilardi, Gianfranco
, p. 277 - 284 (2012)
In order to develop in vitro methods as an alternative to P450 animal testing in the drug discovery process, two main requisites are necessary: 1) gathering of data on animal homologues of the human P450 enzymes, currently very limited, and 2) bypassing t
Synthesis of 6α-hydroxypaclitaxel, the major human metabolite of paclitaxel
Yuan, Haiqing,Kingston, David G. I.
, p. 4967 - 4970 (1998)
6α-Hydroxypaclitaxel, the major human metabolite of paclitaxel, was synthesized via epimerization of 6α-hydroxy-7-epipaclitaxel, which was prepared from paclitaxel in four steps in high yield. Various epimerization conditions were investigated, and the op
In vitro evaluations for pharmacokinetic drug-drug interactions of a novel serotonin-dopamine activity modulator, brexpiprazole
Sasabe, Hiroyuki,Koga, Toshihisa,Furukawa, Masayuki,Matsunaga, Masayuki,Sasahara, Katsunori,Hashizume, Kenta,Oozone, Yoshihiro,Amunom, Immaculate,Torii, Mikako,Umehara, Ken,Kashiyama, Eiji,Takeuchi, Kenji
supporting information, p. 522 - 535 (2021/03/19)
Brexpiprazole, a serotonin-dopamine activity modulator, is indicated for the treatment of schizophrenia and also adjunctive therapy to antidepressants for the treatment of Major Depressive Disorder. To determine the drug–drug interaction risk for cytochrome P450, and SLC and ABC transporters, brexpiprazole and its metabolite, DM-3411 were assessed in this in?vitro investigation. Brexpiprazole exhibited weak inhibitory effects (IC50 >13 μmol/L) on CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activities, but had moderate inhibitor activity on CYP2B6 (IC50 8.19 μmol/L). The ratio of systemic unbound concentration (3.8 nmol/L) to the Ki value was sufficiently low. DM-3411 had comparable inhibitory potentials with brexpiprazole only for CYP2D6 and CYP3A4. The mRNA expressions of CYP1A2, CYP2B6 and CYP3A4 were not changed by the exposure of brexpiprazole to human hepatocytes. Brexpiprazole and DM-3411 exhibited weak or no inhibitory effects for hepatic and renal transporters (OATPs, OATs, OCTs, MATE1, and BSEP), except for MATE-2K (0.156 μmol/L of DM-3411), even for which the ratio to systemic unbound concentration (5.3 nmol/L) was sufficiently low. Brexpiprazole effected the functions of P-gp and BCRP with IC50 values of 6.31 and 1.16 μmol/L, respectively, however, the pharmacokinetic alteration was not observed in the clinical concomitant study on P-gp and BCRP substrates. These in?vitro data suggest that brexpiprazole is unlikely to cause clinically relevant drug interactions resulting from the effects on CYPs or transporters mediating the absorption, metabolism, and/or disposition of co-administered drugs.
Evaluation of Cytochrome P450 Selectivity for Hydralazine as an Aldehyde Oxidase Inhibitor for Reaction Phenotyping
Yang, Xin,Johnson, Nathaniel,Di, Li
, p. 1627 - 1630 (2019/01/16)
Hydralazine has been reported as a selective mechanism-based inactivator of aldehyde oxidase (AO) and it is widely used in the pharmaceutical industry for reaction phenotyping to estimate fraction metabolized by AO and to identify AO substrates. In this study, however, hydralazine was found to inhibit CYP1A2, 2B6, 2D6, and 3A in human suspension hepatocytes under reaction phenotyping assay conditions, at concentrations that chemically knocked out most of the AO activities (≥50 μM). Furthermore, hydralazine is a time-dependent inhibitor of CYP1A2. Based on these findings, precautions need to be taken when using hydralazine as an AO inhibitor for in vitro studies because fraction metabolized by AO is likely to be overestimated and the likelihood of false positives in identifying AO substrates increases.
