Drug-receptor interactions inductive

As shown previously, functional -SH groups seem to be involved in the receptor configuration. However, these receptors are not identical as shown by the comparison of the relation between structure and activity of peptide analogues. A common effect of the peptide on the target organ is the induction of tachyphylaxis according to the actual concepts of drug-receptor interaction, this could be due to a slow dissociation of the peptide from the receptor. 

Stereoselectivity was evident in the assays for stereotyped behavior and PCP receptor interaction, but not in the assay for ataxia as the (+) isomers of the PCP-like drugs and SKF-10,047 were more potent than the (-) isomers in induction of stereotyped behavior and inhibition of binding of 3H-PCP. However, one exception to this trend is that the (-) isomer of cyclazocine was more potent than the (+) isomer in industion of stereotyped behavior and inhibition of the binding of 3H-PCP. 

In those species, which are responsive (i.e., have a functioning receptor) such as the rat, treatment with drugs, which interact with the PPARa receptor such as clofibrate, will cause a number of effects, such as induction of a number of enzymes, increased cell growth and turnover, and liver tumors in almost all the animals as a direct result of interaction with the receptor and changes in gene transcription. This will be discussed in more detail in chapter 7. 

El-Sankary W, Bombail V, Gibson GG, Plant N (2002) Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein DNA interaction distinct from the pregnane X receptor response element. Drug Metab Dispos 30, 1029-1034. 

Waxman DJ (1999) P450 gene induction by structurally diverse xenochemicals central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369 11-23 Yang Y, Blomme EA, Waring JF (2004) Toxicogenomics in drug discovery from preclinical studies to clinical trials. Chem Biol Interact 150 71-85... 

Interactions. Drugs that lower gastric acidity, e.g. antacids, histamine H2 receptor antagonists, impair the absorption of ketoconazole from the gastrointestinal tract. Like all imidazoles, ketoconazole binds strongly to several cytochrome P450 isoenzymes and thus inhibits the metabolism (and increases effects of) oral anticoagulants, phenytoin and cyclosporin, and increases the risk of cardiac arrhythmias with terfenadine. A disulfiram-like reaction occurs with alcohol. Concurrent use of rifampicin, by enzyme induction of CYP 3A, markedly reduces the plasma concentration of ketoconazole. 

---