Ann-Charlotte Egnell

AstraZeneca, Tukholma, Stockholm, Sweden

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Publications (3)11.67 Total impact

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    Ann-Charlotte Egnell, J Brian Houston, C Scott Boyer
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    ABSTRACT: 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. The antimalarial artemisinin potently increases CBZ-ep formation by a maximum of 500% at 300 microM. Testosterone and progesterone activates by a maximum of 1680 and 920%, respectively, at 150 microM, and quinidine causes a 130% increase at 300 microM. The predicted maximum in vivo decrease in steady-state concentration of carbamazepine (Css(CBZ)) at saturating effector concentrations is 85 to 90% for testosterone and progesterone, 75% for artemisinin, and 45% for quinidine. The corresponding predicted in vivo increase in Css(CBZ-ep) is 50, 60, 55, and 30% for artemisinin, testosterone, progesterone, and quinidine, respectively. At effector concentrations relevant in vivo, the Css(CBZ) change is predicted to </=20% for testosterone, artemisinin, and quinidine and </=10% for progesterone, with a concomitant Css(CBZ-ep) increase of 12% for testosterone and </=10% for progesterone, artemisinin, and quinidine. Structure-heteroactivation relationships were evaluated by generating a pharmacophore. The model includes two hydrogen bond acceptor features separated by hydrophobic features. Internal predictivity is high, and heteroactivation of an external test set correlate to observed in vitro heteroactivation.
    Journal of Pharmacology and Experimental Therapeutics 04/2005; 312(3):926-37. · 3.89 Impact Factor
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    ABSTRACT: Positive cooperativity (auto- and heteroactivation) of drug oxidation, a potential cause of drug interactions, is well established in vitro for cytochrome P450 (P450) 3A4 but to a much lesser extent for other drug-metabolizing P450 isoforms. Using a high throughput fluorescent-based CYP2C9 effector assay, we identified >30 heteroactivators from a set of 1504 structurally diverse compounds. Several potent heteroactivators of CYP2C9-mediated 7-methoxy-4-trifluoromethyl-coumarin metabolism are marketed drugs or endogenous compounds (amiodarone, niclosamide, liothyronine, meclofenemate, zafirlukast, estropipate, and dichlorphenamide, yielding 150% control reaction velocity at 0.04, 0.09, 0.5, 1, 1.2, 1.5, and 2.5 microM, respectively). Some heteroactivators are also known CYP2C9 substrates or inhibitors, suggesting potential multiple binding sites and substrate-dependent effects. v(150%), the concentration of effector giving 150% of control reaction velocity, was used as pharmacophore modeling parameter based on enzyme kinetic assumptions. The generated pharmacophore (training set: n = 36, v(150%) 0.04-150 microM) contains one hydrogen bond acceptor, one aromatic ring, and two hydrophobes. v(150%) values for 94% of the training set heteroactivators were predicted within 1 log unit for the residual (r [log observed v(150%)] versus [log predicted v(150%)] = 0.71; r2 0.50). The model also correctly identifies close to 70% of potent inhibitors (IC50 < 1 microM) as high-affinity CYP2C9 binders, suggesting that heteroactivators and inhibitors share some common structural CYP2C9 binding features, supporting the previously suggested hypothesis that CYP2C9 heteroactivators can bind within the active site.
    Journal of Pharmacology and Experimental Therapeutics 12/2003; 307(3):878-87. · 3.89 Impact Factor
  • Ann-Charlotte Egnell, Brian Houston, Scott Boyer
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    ABSTRACT: Atypical (non-Michaelis-Menten) kinetics are commonly observed with CYP3A4 substrates in vitro. If relevant in vivo, cytochrome P450 heteroactivation could give rise to increased drug clearance. To test the possible in vivo relevance of atypical cytochrome P450 kinetics, we investigated the role of heteroactivation in the therapeutically relevant drug interaction between the anti-epileptics felbamate and carbamazepine. Felbamate heteroactivates CYP3A4-mediated formation of carbamazepine-10,11-epoxide (carbamazepine-ep), the major metabolite of carbamazepine, in human liver microsomes and recombinant CYP3A4 at relevant in vivo concentrations of both drugs (maximum activation 98% at 10 microM carbamazepine, 1 mM felbamate). Felbamate (50-500 microM) did not induce CYP3A4, as based on mRNA measurements in human liver slices. The further metabolism of carbamazepine-ep was inhibited (38% by 500 microM felbamate) in human liver slices. We propose a methodology to predict changes in steady-state plasma concentrations (Css) of parent drug and metabolite from in vitro heteroactivation and inhibition data, including prediction of the increase in fraction metabolized. A meta-analysis of reported in vivo effects of felbamate on Csscarbamazepine was performed to allow evaluation of this approach. The predicted effect of in vitro heteroactivation on Csscarbamazepine corresponds well to that observed in vivo. Combining the effect of heteroactivation on the fraction metabolized to carbamazepine-ep, and inhibition of its further metabolism, predicts a change in Csscarbamazepine-ep that falls within the range observed in vivo. Our results strongly suggest that in vivo heteroactivation of CYP3A4 is a possible mechanism of the clinically observed drug interaction between felbamate and carbamazepine.
    Journal of Pharmacology and Experimental Therapeutics 07/2003; 305(3):1251-62. · 3.89 Impact Factor