Cytochrome P-450 CYP3A

Publication Title: 
Phytomedicine: International Journal of Phytotherapy and Phytopharmacology

This study investigated the effect of Danshen on the pharmacodynamic-pharmacokinetic (PD-PK) effects of midazolam, a model CYP3A probe substrate. The effects of acute and 3-day Danshen treatment on the pharmacokinetics of a low dose midazolam (10 mg/kg, i.p.) were determined in vivo in the rat. Danshen (200 mg/kg, i.p.) treatment decreased midazolam clearance by 16%, with increases in the AUC by 22% and the half-life by 14%. 3-Day Danshen treatment (200 mg/kg/day, i.p.) for 3 days decreased the clearance, with increases in the T(1/2) and AUC.

Wang, Xin
Lee, Wayne Y. W.
Zhou, Xuelin
Or, Penelope M. Y.
Yeung, John H. K.
Publication Title: 
British Journal of Clinical Pharmacology

AIMS: The study aimed to identify the specific human cytochrome P450 (CYP450) enzymes involved in the metabolism of artemisinin. METHODS: Microsomes from human B-lymphoblastoid cell lines transformed with individual CYP450 cDNAs were investigated for their capacity to metabolize artemisinin. The effect on artemisinin metabolism in human liver microsomes by chemical inhibitors selective for individual forms of CYP450 was investigated.

Svensson, U. S.
Ashton, M.
Publication Title: 
The Journal of Pharmacology and Experimental Therapeutics

Although activation of CYP3A4 is frequently observed in vitro, predictive computational-based models and methods for in vitro-in vivo scaling are scarce. It has been previously shown that in vitro CYP3A4 heteroactivation of carbamazepine (CBZ)-epoxide (ep) formation can be associated with the clinical drug interaction between felbatame and CBZ. The previously reported prediction methodology is applied here to an additional set of in vitro CYP3A4 heteroactivators, some exerting this effect at concentrations relevant in vivo.

Egnell, Ann-Charlotte
Houston, J. Brian
Boyer, C. Scott
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

Artemether (AM) is one of the most effective antimalarial drugs. The elimination half-life of AM is very short, and it shows large interindividual variability in pharmacokinetic parameters. The aim of this study was to identify cytochrome P450 (P450) isozymes responsible for the demethylation of AM and to evaluate functional differences between 26 CYP2B6 allelic variants in vitro. Of 14 recombinant P450s examined in this study, CYP2B6 and CYP3A4 were primarily responsible for production of the desmethyl metabolite dihydroartemisinin.

Honda, Masashi
Muroi, Yuka
Tamaki, Yuichiro
Saigusa, Daisuke
Suzuki, Naoto
Tomioka, Yoshihisa
Matsubara, Yoichi
Oda, Akifumi
Hirasawa, Noriyasu
Hiratsuka, Masahiro
Publication Title: 
Antimicrobial Agents and Chemotherapy

Artemisinins induce drug metabolism through the activation of the pregnane X receptor (PXR) in vitro. Here, we report the resequencing and genotyping of PXR variants in 75 Vietnamese individuals previously characterized for CYP3A enzyme activity after artemisinin exposure. We identified a total of 31 PXR variants, including 5 novel single nucleotide polymorphisms (SNPs), and we identified significantly different allele frequencies relative to other ethnic groups.

Piedade, Rita
Schaeffeler, Elke
Winter, Stefan
Asimus, Sara
Schwab, Matthias
Ashton, Michael
Burk, Oliver
Gil, José P.
Publication Title: 
British Journal of Pharmacology

BACKGROUND AND PURPOSE: Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug-drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH: A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking.

Burk, O.
Piedade, R.
Ghebreghiorghis, L.
Fait, J. T.
Nussler, A. K.
Gil, J. P.
Windshügel, B.
Schwab, M.
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

Artemisinin drugs have become the first-line antimalarials in areas of multidrug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of cytochrome P450 (P450)-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism.

Xing, Jie
Kirby, Brian J.
Whittington, Dale
Wan, Yakun
Goodlett, David R.
Publication Title: 
Malaria Journal

BACKGROUND: Artequick is a relatively inexpensive artemisinin (Qing-hao-su; QHS)-based combination therapy (ACT) that contains QHS and piperaquine (PQ), which has not been widely used because of the decreased concentration level of QHS after repeated oral administrations for five to seven days as a monotherapy. This study was designed to evaluate the potential auto-induction metabolism of QHS in healthy Chinese adults after a two-day oral administration of QHS-PQ. The effect of QHS-PQ on the activity of the CYP2B6 and CYP3A4 was also investigated.

Zang, Meitong
Zhu, Fanping
Li, Xinxiu
Yang, Aijuan
Xing, Jie
Publication Title: 
PloS One

Bacopa monniera is a traditional Ayurvedic herbal medicine used to treat various mental ailments from ancient times. Recently, chemically standardized alcoholic extract of Bacopa monniera (BM) has been developed and currently available as over the counter herbal remedy for memory enhancement in children and adults. However, the consumption of herbal drugs has been reported to alter the expression of drug metabolizing enzymes and membrane transporters.

Singh, Rajbir
Panduri, Jagadeesh
Kumar, Devendra
Kumar, Deepak
Chandsana, Hardik
Ramakrishna, Rachumallu
Bhatta, Rabi Sankar
Publication Title: 
Journal of Ethnopharmacology

ETHNOPHARMACOLOGICAL RELEVANCE: 'Triphala' is one of the age-old, most commonly used polyherbal preparation from Ayurveda as Rasayana drug. AIM OF THE STUDY: This study was aimed at evaluating the effect of 'Triphala' on drug modulating enzymes to assess its safety through its potential to interact with co-administered drugs. MATERIALS AND METHODS: The cytochrome P450 inhibitory effect of 'triphala' formulation was investigated on rat liver microsomes using CYP450-CO complex assay and on individual isoform such as CYP3A4 and 2D6 using fluorescence screening.

Ponnusankar, S.
Pandit, Subrata
Babu, Ramesh
Bandyopadhyay, Arun
Mukherjee, Pulok K.


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