title: Flavonoids and polymer derivatives as CYP3A4 inhibitors for improved oral drug bioavailability.
abstract: Molecular modeling computations were utilized to generate pharmaceutical grade CYP3A4-enzyme inhibitors. In vitro metabolism of felodipine in human intestinal and liver microsomes (HLM and HIM) was optimized yielding a Michaelis-Menten plot from where the K(m) and V(max) values were estimated by nonlinear regression. The flavonoids, naringin, naringenin, and quercetin, were subsequently incubated with felodipine at the determined K(m) value in HLM. Comparing results obtained from a known CYP3A4 inhibitor, verapamil, the flavonoids inhibited felodipine metabolism. In-depth computational analysis of these flavonoids in terms of CYP3A4 binding, sequencing, and affinity, computational biomimetism was employed to validate the potential CYP3A4 inhibitors. The modeled compounds were comparatively evaluated by incubation with felodipine in both HLM and HIM. Results showed that the polymers 8-arm-PEG, o-(2-aminoethyl)-o-methyl-PEG, 4-arm-PEG (molecular weight = 10,000 g/mol and 20,000 g/mol, respectively), and poly(l-lysine) were able to inhibit the felodipine metabolism with the half maximal inhibitory concentration (IC(50)) values ranging from 7.22 to 30.0 μM (HLM) and 5.78 to 41.03 μM (HIM). Molecular docking confirmed drug-enzyme interactions by computing the free energies of binding (ΔE) and inhibition constants (K(i)) of the docked compounds utilizing a Lamarckian Genetic Algorithm. Comparative correlations between the computed and experimental K(i) values were obtained. Computational modeling of CYP3A4 inhibitors provided a suitable strategy to screen pharmaceutical grade compounds that may potentially inhibit presystemic CYP3A4-dependent drug metabolism with the prospect of improving oral drug bioavailability.
authors.affiliation: University of the Witwatersrand, Faculty of Health Sciences, Department of Pharmacy and Pharmacology, Johannesburg 2193, South Africa.
authors.forename: Pius
authors.initials: P
authors.lastname: Fasinu
authors.forename: Yahya E
authors.initials: YE
authors.lastname: Choonara
authors.forename: Riaz A
authors.initials: RA
authors.lastname: Khan
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Du Toit
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.forename: Valence M K
authors.initials: VM
authors.lastname: Ndesendo
authors.forename: Viness
authors.initials: V
authors.lastname: Pillay
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D055815:Young Adult
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D011108:Polymers; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human