Anti-CYP3A4 monoclonal antibody, clone 602DU27.2.2

Voriconazole is the first-line drug for invasive aspergillosis infection treatment. It is metabolized via cytochrome P450 2C19 (CYP2C19), cytochrome P450 3A4 (CYP3A4) and flavin-containing monooxygenase 3 (FMO3). Many studies revealed the correlation between genetic polymorphisms of these SNPs and voriconazole metabolism. Several mutations, however, have not been reported in Thai population. Therefore, this study investigated the prevalence of CYP2C19, CYP3A4 and FMO3 polymorphisms. Two hundred and forty-nine healthy northeastern Thai volunteers who were blood donors at Srinagarind Hospital blood bank were enrolled. CYP2C19 (*2, *3, *17), CYP3A4 (*22, rs4646437G>A) and FMO3 (rs2266782G>A, rs2266780A>G) mutations were investigated. The allele frequencies were CYP2C19*1 (0.72), *2 (0.24), *3 (0.03) and *17 (0.02) in this study. They were significantly different from Caucasian and Japanese populations. Moreover, CYP3A4 rs4646437 allele frequencies were 0.76 for "G" and 0.24 for "A" alleles. The mutation of CYP3A4*22 was not found in this study. Wild type (G) and mutation (A) allele frequencies of FMO3 rs2266782 were 0.86 and 0.14, respectively. Similarly, the allele frequencies of FMO3 rs2266780 for "A" (wild type) and "G" (mutant) were 0.89 and 0.11, respectively. Furthermore, a strong linkage disequilibrium was found between FMO3 rs2266782 and rs2266780 genes (D' = 0.955, r(2) = 0.7021). The information on the SNP frequencies of CYP2C19, CYP3A4 and FMO3 in Thais was found to be significantly different from other populations. The genotype prevalence may be the preliminary information for a further clinical study to investigate the association between these genotypes and voriconazole treatment outcomes.

To investigate the beneficial effects of oridonin, a diterpenoid compound isolated from Rabdosia rubescens, on the inflammatory response in TNBS-induced post-inflammatory irritable bowel syndrome (PI-IBS) model and the underlying mechanism. Using the PI-IBS rat model and Caco-2 cell lines, we found that intestinal barrier function reflected by lactulose/mannitol (L/M) ratio and tight junction protein level was significantly ameliorated by oridonin. We also demonstrated that oridonin abrogated inflammation through inhibiting the phosphorylation of NF-kappa Bp65 as well as its downstream gene (iNOS, COX-2, IL-1 beta, and IL-6) level. Molecular docking studies confirmed the good binding activity between oridonin and PXR. In Caco-2 cell lines, oridonin markedly inhibited LPS-induced NF-kappa B activation in a PXR-dependent manner. Meanwhile, PXR and its target genes CYP3A4 and P-gp were induced by oridonin, which was associated with the decreased expression of NF-kappa B and the recovery of intestinal barrier. This study indicated that the therapeutic effect of oridonin on experimental PI-IBS through repairing intestinal barrier function may be closely associated with the regulatory role of PXR/NF-kappa B signaling pathway. Oridonin may serve as a PXR ligand for the development of drugs in the therapy for PI-IBS.