Direct Interaction between Substrates and Endogenous Steroids in the Active Site May Change the Activity of Cytochrome P450 3A4

Torimoto, Nao; Ishii, Itsuko; Hata, Masayuki; Nakamura, Hiroyoshi; Imada, Hiroshi; Ariyoshi, Noritaka; Ohmori, Shigeru; Isobe, Takashi; Kitada, Munehiro

doi:10.1021/bi034409n

Cited by 46 publications

(36 citation statements)

References 30 publications

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“…Effectors such as testosterone and ␣-naphthoflavone and possibly the spices that showed differential effects on 1Ј-OH-MDZ and 4-OH-MDZ formation could bind at sites that effectively block access to at least one but not all of the possible MDZ-binding sites. Kinetic models (Shou et al, 2001) and theoretical molecular models (Torimoto et al, 2003) have been developed to account for the allosteric interaction within the CYP3A4 active site. These models have attempted to differentiate between two substrates simultaneously bound to the active site, substrates competing for the active site, and changes activated by binding of an effector at a site other than the active site.…”

Section: Discussionmentioning

confidence: 99%

Effects of Spice Constituents on P-Glycoprotein-Mediated Transport and CYP3A4-Mediated Metabolism in Vitro

Zhang

Lim²

2008

Drug Metab Dispos

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Section: Discussionmentioning

confidence: 99%

Effects of Spice Constituents on P-Glycoprotein-Mediated Transport and CYP3A4-Mediated Metabolism in Vitro

Zhang

Lim²

2008

Drug Metab Dispos

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“…1). Some previous studies have investigated the in vitro heteroactivation phenomenon using only a single arbitrarily selected high substrate concentration (Nakamura et al, 2002;Torimoto et al, 2003), which might not provide a true estimation of the extent of heteroactivation. Moreover, it should be noted that concentrations of drugs in both in vitro drug metabolic stability studies and in vivo in plasma are usually in the low micromolar region.…”

Section: Discussionmentioning

confidence: 99%

“…However, previous studies reporting heteroactivation (Nakamura et al, 2002Torimoto et al, 2003) have been limited in design, using either a single high effector concentration (Ն100 M) or a single in vitro system. The lack of studies covering a range of effector concentrations, particularly encompassing physiological values, confounds any conclusions on the in vivo relevance of heteroactivation.…”

mentioning

confidence: 99%

Comparative Analysis of CYP3A Heteroactivation by Steroid Hormones and Flavonoids in Different in Vitro Systems and Potential in Vivo Implications

Henshall

Galetin²,

Harrison

et al. 2008

Drug Metab Dispos

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ABSTRACT:A systematic analysis of the heteroactivation of CYP3A-mediated carbamazepine 10,11-epoxidation has been investigated in three different in vitro systems, namely recombinant CYP3A4 and CYP3A5, human liver microsomes (HLMs) and cryopreserved human hepatocytes. The effect of 10 endogenous steroids and flavonoids was studied over a range of substrate and effector concentrations. A novel heteroactivation model was used to obtain the parameters EC 200 (concentration of effector required to produce 200% control) and heteroactivation ratio (the ratio of maximum observed reaction velocity to control). The EC 200 values obtained in HLMs and human hepatocytes were corrected for nonspecific binding. Heteroactivation of CYP3A5 has been demonstrated with mean heteroactivation ratios in CYP3A5, HLMs and hepatocytes on average 2-fold greater than in recombinant CYP3A4 for most of the effectors investigated. In recombinant CYP3A4, heteroactivation was greatest at substrate concentrations below K m . Heteroactivation increased with effector concentration in a nonlinear manner and differed between effectors (mean heteroactivation ratios varied up to 12-fold). A greater extent of heteroactivation was observed in HLMs than in human hepatocytes for steroid effectors, but the opposite was true for flavonoid effectors. The observed heteroactivation of CYP3A in intact cells supports an in vivo relevance. From the in vitro heteroactivation data, a significant increase in clearance in vivo was predicted for substrates with a high dependence on CYP3A4 to the overall elimination, indicating that heteroactivation of CYP3A may be a potential source of interindividual variability.Cytochromes P450 (P450s) 3A are the most abundant P450 enzymes in the human liver and small intestine (Paine et al., 2006). In vitro assays of CYP3A-mediated metabolism are used routinely in the drug discovery effort to quantitatively predict in vivo pharmacokinetic parameters. However, these estimates may be confounded by atypical (non-Michaelis-Menten) kinetics such as autoactivation (homotropic cooperativity, evident as a sigmoidal kinetic profile), heteroactivation (heterotropic cooperativity, the activation of a substrate's metabolism by a separate effector compound), or substrate inhibition (inhibition of a substrate's own metabolism) (Houston and Galetin, 2005). A number of studies have addressed the issue of atypical kinetics (Tang and Stearns, 2001;Davydov et al., 2007). Heteroactivation is displayed by a number of CYP3A substrates in vitro, including the antiepileptic, carbamazepine (Nakamura et al., 2002;Egnell et al., 2003a). Heteroactivator-enzyme interaction has been rationalized either by the simultaneous binding of substrate and effector molecules (Shou et al., 1994) or assuming the existence of a separate effector-binding site (Houston and Galetin, 2005).Evidence exists that heteroactivation of CYP3A may occur in vivo. Coadministration of quinidine resulted in an acute increase in diclofenac clearance in monkeys, an effect also observed in m...

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“…Furthermore, endogenous steroids have been shown to activate CYP3A4 mediated metabolism and interactions by some drugs (e.g. nevirapine) with endogenous steroids in the active site of CYP3A4 can alter the activity of this isoenzyme [32]. For example, nevirapine 2-hydroxylation was strongly activated by many endogenous steroids including testosterone [32].…”

Section: Discussionmentioning

confidence: 99%

“…nevirapine) with endogenous steroids in the active site of CYP3A4 can alter the activity of this isoenzyme [32]. For example, nevirapine 2-hydroxylation was strongly activated by many endogenous steroids including testosterone [32]. The effect of testosterone and nandrolone on ART metabolism is yet to be rigorously investigated.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic drug monitoring of atazanavir: surveillance of pharmacotherapy in the clinic

Ray

Marriott

Bloch³

et al. 2005

Brit J Clinical Pharma

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BackgroundTherapeutic failure with antiretroviral therapy (ART) is a substantial issue where viral rebound, viral resistance and drug-related toxicity remain serious concerns. Drug exposure-response relationships have been described for the protease inhibitors, pharmacokinetic variability is substantial for this class of drugs and drug interactions can also alter ART exposure. Given this background we established a therapeutic drug monitoring (TDM) service to monitor atazanavir (ATV) plasma concentrations early after the therapy was made available to treatment-experienced people infected with HIV who were managed in a clinical setting. MethodsThis was a prospective observational study which evaluated plasma samples from 110 highly treatment-experienced people with HIV using TDM and applied pharmacokinetic analysis over a five month period. ResultsATV trough concentrations exhibited substantial intersubject variability ( < 25-2108 m g l -1 ). A substantial number of subjects (50%,13/26) who received ATV400 mg daily had low exposure to ATV. Serum bilirubin concentrations correlated significantly with higher ATV trough concentrations ( r = 0.803; P < 0.001) and 55% (29/53) of subjects who received ATV300/100 mg RTV daily had plasma concentrations above a proposed target concentration associated with elevated bilirubin concentrations. This study confirmed low ATV exposure in eight subjects with HIV receiving ATV 400 mg daily. Reasons for low ATV exposure in this cohort include administration of interacting drugs, including a possible interaction with ritonavir, fluticasone and ATV, impaired ATV absorption secondary to suspected achlorhydria and potential interactions with colchicine and nandrolone. Viral load remained undetectable in most of these subjects with low ATV exposure. ConclusionsTDM and targeted pharmacokinetic studies should be viewed as fundamental tools in the development and clinical application of ART, to improve pharmacotherapy for people with HIV.J. E. Ray et al. 29260 :3 Br J Clin Pharmacol

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Direct Interaction between Substrates and Endogenous Steroids in the Active Site May Change the Activity of Cytochrome P450 3A4

Cited by 46 publications

References 30 publications

Effects of Spice Constituents on P-Glycoprotein-Mediated Transport and CYP3A4-Mediated Metabolism in Vitro

Effects of Spice Constituents on P-Glycoprotein-Mediated Transport and CYP3A4-Mediated Metabolism in Vitro

Comparative Analysis of CYP3A Heteroactivation by Steroid Hormones and Flavonoids in Different in Vitro Systems and Potential in Vivo Implications

Therapeutic drug monitoring of atazanavir: surveillance of pharmacotherapy in the clinic

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