Heterotropic allosteric modulation of CYP3A4 in vitro by progesterone: Evidence for improvement in prediction of time-dependent inhibition for macrolides.

Predictions of drug-drug interactions resulting from time-dependent inhibition (TDI) of CYP3A4 have consistently overestimated or mispredicted (ie, false positives) the interaction that is observed in vivo. Recent findings demonstrated that the presence of the allosteric modulator progesterone (PGS) in the in vitro assay could alter the in vitro kinetics of CYP3A4 TDI with inhibitors that interact with the heme moiety, such as metabolic-intermediate complex forming inhibitors. The impact of the presence of 100 μM PGS on the TDI of molecules in the class of macrolides typically associated with metabolic-intermediate complex formation was investigated.

Heterotropic Allosteric Modulation of CYP3A4 In Vitro by Progesterone: Evidence for Improvement in Prediction of Time Dependent Inhibition for Macrolides.

Predictions of drug-drug interactions resulting from time-dependent inhibition (TDI) of CYP3A4 have consistently overestimated or mis-predicted (i.e. false positives) the interaction that is observed in vivo.

Impact of Heterotropic Allosteric Modulation on the Time-Dependent Inhibition of Cytochrome P450 3A4.

The current study was designed to investigate the influence of allosteric effectors on the metabolism of the prototypical cytochrome P450 (CYP) 3A4 substrate midazolam (MDZ), and on the determination in vitro time-dependent inhibition (TDI) of CYP3A4 using human liver microsomes (HLM). As the concentration of midazolam increased to 250 M in HLMs, homotropic cooperativity resulted in a decrease in the 1'-hydroxymidazolam to 4-hydroxymidazolam ratio to a maximum of 1.1.

Chronic Exposure to 4-Nonylphenol Alters UDP-Glycosyltransferase and Sulfotransferase Clearance of Steroids in the Hard Coral, .

The effects of the xenoestrogen 4-nonylphenol (4NP) on endocrine and metabolic homeostasis in the reef building coral, were investigated. The aim was to understand if ubiquitous nonylphenol ethoxylate contaminants in the marine environment result in altered homeostatic function. Coral colonies were chronically exposed (6 weeks) to a sublethal concentration (1 ppb) of 4NP and sampled over the coral's lunar reproductive cycle.

The Impact of the Hepatocyte-to-Plasma pH Gradient on the Prediction of Hepatic Clearance and Drug-Drug Interactions for CYP2C9 and CYP3A4 Substrates.

Surrogate assays for drug metabolism and inhibition are traditionally performed in buffer systems at pH 7.4, despite evidence that hepatocyte intracellular pH is 7.0.