Pharmacokinetics Of Medicines Research Articles

Effect of the Arg456His mutation on the three-dimensional structure of cytochrome P450 1A2 predicted by molecular dynamics simulations

Cytochrome P450 1A2 (CYP1A2), one of the major drug-metabolizing enzymes among CYPs, has many variant alleles. The genetic polymorphism of CYP1A2 is thought to cause individual differences in the pharmacokinetics of medicines. CYP1A2.8 (the Arg456His mutant), a CYP1A2 variant, has decreased enzymatic activity. In our previous work, to understand why the Arg456His mutant lost its enzymatic activity, we constructed an Arg456His mutant with the hydrogen on the epsilon nitrogen of the histidine (HIE) and performed a 300-ns MD simulation. After the MD simulation, the Arg456His mutant with HIE showed large differences in static structure and flexibility compared with the wild type, which would cause the decreased activity. In the work described here, we constructed an additional Arg456His mutant with positively charged histidine and performed a 300-ns MD simulation to consider the effect of the protonation state of the histidine. Comparing these two Arg456His mutants revealed differences in their static structures, flexibilities, and interactions, suggesting that the protonation state of the His456 residue has a considerable influence on the physiological properties of CYPs. Our results indicate that the Arg456His mutation causes the CYP1A2 structure to unfold regardless of the protonation state of His456.

Prediction of three-dimensional structures and structural flexibilities of wild-type and mutant cytochrome P450 1A2 using molecular dynamics simulations

In this study, we investigated the effect of genetic polymorphism on the three-dimensional (3D) conformation of cytochrome P450 1A2 (CYP1A2) using molecular dynamics (MD) simulations. CYP1A2, a major drug-metabolizing enzyme among cytochrome P450 enzymes (CYPs), is known to have many variant alleles. The genetic polymorphism of CYP1A2 may cause individual differences in the pharmacokinetics of medicines. By performing 100ns or longer MD simulations, we investigated the influence of amino acid mutation on the 3D structures and the dynamic properties of proteins. The results show that the static structures were changed by the mutations of amino acid residues, not only near the mutated residues but also in distant portions of the proteins. Moreover, the mutation of only one amino acid was shown to change the structural flexibility of proteins, which may influence the substrate recognition and enzymatic activity. Our results clearly suggest that it is necessary to investigate the dynamic property as well as the static 3D structure for understanding the change of the enzymatic activity of mutant CYP1A2.

Synthesis, biological evaluation and 3D-QSAR studies of new chalcone derivatives as inhibitors of human P-glycoprotein

P-glycoprotein (P-gp) is an ATP-dependent multidrug resistance efflux transporter that plays an important role in anticancer drug resistance and in pharmacokinetics of medicines. Despite a large number of structurally and functionally diverse compounds, also flavonoids and chalcones have been reported as inhibitors of P-gp. The latter share some similarity with the well studied class of propafenones, but do not contain a basic nitrogen atom. Furthermore, due to their rigidity, they are suitable candidates for 3D-QSAR studies. In this study, a set of 22 new chalcone derivatives were synthesized and evaluated in a daunomycin efflux inhibition assay using the CCRF.CEM.VCR1000 cell line. The compound 10 showed the highest activity (IC50=42nM), which is one order of magnitude higher than the activity for an equilipohillic propafenone analogue. 2D- and 3D-QSAR studies indicate the importance of H-bond acceptors, methoxy groups, hydrophobic groups as well as the number of rotatable bonds as pharmacophoric features influencing P-gp inhibitory activity.

Role of pharmacogenomics for understanding large inter-individual differences in clinical responses and pharmacokinetics of medicines

Role of pharmacogenomics for understanding large inter-individual differences in clinical responses and pharmacokinetics of medicines

Effects of Sweetie Juice on Nifedipine Pharmacokinetics in Rats

It has been reported that grapefruit juice (GJ) causes pharmacokinetic interactions with many drugs after co-ingestion, but the effects of the juice of sweetie fruit, a cross between a pomelo and a grapefruit, on the pharmacokinetics of medicines have not been clear. The present study investigated the drug interaction capability of sweetie juice (SJ). The effect of SJ on nifedipine (NFP) pharmacokinetics in rats was studied. Two milliliters of SJ, GJ, or saline was administered to the rat duodenum. After 30 min, NFP was administered intraduodenally at a dose of 3 mg/kg body weight. The NFP concentrations in the plasma samples were determined by high performance liquid chromatography (HPLC). Although GJ increased the area under the plasma concentration-time curve (AUC) of NFP (1.6-fold), SJ had no significant effect on the NFP pharmacokinetics in rats. Furthermore, concentrations of furanocoumarin derivatives in SJ were measured by HPLC equipped with a photodiode array detector, and compared with those in GJ. SJ contained lower concentrations of bergamottin (0.53 microg/ml), 6', 7'-dihydroxybergamottin (0.19 microg/ml), and bergaptol (0.2 microg/ml) than the GJ used in this study (6.3 microg/ml, 3.6 microg/ml, and 9.4 microg/ml, respectively). In conclusion, the results suggest that SJ had no effect on the NFP pharmacokinetics in rats due to low furanocoumarin concentrations in SJ.