ABSTRACT
Monkeys have been proposed as an animal model to predict the magnitude of human clinical drug-drug interactions caused by CYP3A4 enzyme induction. To evaluate whether the cynomolgus monkey can be an effective in vivo model, human CYP3A4 inducers were evaluated both in vitro and in vivo. First, a full-length pregnane X receptor (PXR) was cloned from the cynomolgus monkey, and the sequence was compared with those of rhesus monkey and human PXR. Cynomolgus and rhesus monkey PXR differed by only one amino acid (A68V), and both were highly homologous to human PXR (approximately 96%). When the transactivation profiles of 30 compounds, including known inducers of CYP3A4, were compared between cynomolgus and human PXR, a high degree of correlation with EC(50) values was observed. These results suggest that cynomolgus and human PXR respond in a similar fashion to these ligands. Second, two known human CYP3A4 inducers, rifampicin and hyperforin, were tested in monkey and human primary hepatocytes for induction of CYP3A enzymes. Both monkey and human hepatocytes responded similarly to the inducers and resulted in increased RNA and enzyme activity changes of CYP3A8 and CYP3A4, respectively. Lastly, in vivo induction of CYP3A8 by rifampicin and hyperforin was shown by significant reductions of midazolam exposure that were comparable with those in humans. These results show that the cynomolgus monkey can be a predictive in vivo animal model of PXR-mediated induction of human CYP3A4 and can provide a useful assessment of the resulting pharmacokinetic changes of affected drugs.
Subject(s)
Cytochrome P-450 CYP3A/biosynthesis , Hepatocytes/metabolism , Macaca fascicularis , Receptors, Steroid/metabolism , Xenobiotics/pharmacokinetics , Adult , Amino Acid Sequence , Animals , Bridged Bicyclo Compounds/blood , Bridged Bicyclo Compounds/pharmacokinetics , Bridged Bicyclo Compounds/pharmacology , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Cloning, Molecular , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Drug Interactions/genetics , Enzyme Induction/drug effects , Enzyme Induction/genetics , Female , Gene Expression/drug effects , Gene Expression/genetics , Hepatocytes/drug effects , Hepatocytes/enzymology , Humans , Hypericum/chemistry , Macaca mulatta , Male , Midazolam/blood , Midazolam/metabolism , Midazolam/pharmacokinetics , Middle Aged , Models, Animal , Molecular Sequence Data , Phloroglucinol/analogs & derivatives , Phloroglucinol/blood , Phloroglucinol/pharmacokinetics , Phloroglucinol/pharmacology , Plant Extracts/blood , Plant Extracts/pharmacokinetics , Pregnane X Receptor , Receptors, Steroid/genetics , Rifampin/blood , Rifampin/pharmacokinetics , Rifampin/pharmacology , Sequence Homology, Amino Acid , Terpenes/blood , Terpenes/pharmacokinetics , Terpenes/pharmacology , Transcriptional Activation/drug effects , Transcriptional Activation/genetics , TransfectionABSTRACT
The SXR humanized mouse model was used to quantitatively assess an in vivo induction response of the human PXR agonist, rifampicin. Three days of rifampicin treatment increased RNA expression and microsomal enzyme activity of CYP3A11, as well as significantly reduced triazolam plasma exposure. These results indicate that the humanized SXR mouse can be used as a model to predict human CYP3A4 induction and the resulting pharmacokinetic changes of CYP3A4 substrates in humans.
Subject(s)
Cytochrome P-450 CYP3A/drug effects , Membrane Proteins/drug effects , Receptors, Steroid/agonists , Rifampin/pharmacology , Animals , Antibiotics, Antitubercular/administration & dosage , Antibiotics, Antitubercular/pharmacology , Cytochrome P-450 CYP3A/metabolism , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Induction/drug effects , Gene Expression Regulation, Enzymologic/drug effects , Humans , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Models, Animal , Pregnane X Receptor , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rifampin/administration & dosage , Species Specificity , Triazolam/pharmacokineticsABSTRACT
The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.
