• Home
  • Search Results
  • Physicochemical space for optimum oral bioavailability: contribution of human intestinal absorption and first-pass elimination.

Physicochemical space for optimum oral bioavailability: contribution of human intestinal absorption and first-pass elimination.

Journal of medicinal chemistry (2010-01-15)
Manthena V S Varma, R Scott Obach, Charles Rotter, Howard R Miller, George Chang, Stefanus J Steyn, Ayman El-Kattan, Matthew D Troutman
ABSTRACT

Oral bioavailability (F) is a product of fraction absorbed (Fa), fraction escaping gut-wall elimination (Fg), and fraction escaping hepatic elimination (Fh). In this study, using a database comprised of Fa, Fg, Fh, and F values for 309 drugs in humans, an analysis of the interrelation of physicochemical properties and the individual parameters was carried out in order to define the physicochemical space for optimum human oral bioavailability. Trend analysis clearly indicated molecular weight (MW), ionization state, lipophilicity, polar descriptors, and free rotatable bonds (RB) influence bioavailability. These trends were due to a combination of effects of the properties on Fa and first-pass elimination (Fg and Fh). Higher MW significantly impacted Fa, while Fg and Fh decreased with increasing lipophilicity. Parabolic trends were observed for bioavailability with polar descriptors. Interestingly, RB has a negative effect on all three parameters, leading to its pronounced effect on bioavailability. In conclusion, physicochemical properties influence bioavailability with typically opposing effects on Fa and first-pass elimination. This analysis may provide a rational judgment on the physicochemical space to optimize oral bioavailability.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Caffeine, powder, ReagentPlus®
Sigma-Aldrich
Dexamethasone, powder, BioReagent, suitable for cell culture, ≥97%
Sigma-Aldrich
Dexamethasone, ≥98% (HPLC), powder
Sigma-Aldrich
Ibuprofen, ≥98% (GC)
Sigma-Aldrich
Rifampicin, ≥97% (HPLC), powder
Sigma-Aldrich
Ciprofloxacin, ≥98% (HPLC)
Sigma-Aldrich
Ampicillin, anhydrous, 96.0-102.0% (anhydrous basis)
Sigma-Aldrich
(−)-Nicotine, ≥99% (GC), liquid
Sigma-Aldrich
Indomethacin, 98.5-100.5% (in accordance with EP)
Sigma-Aldrich
Hydroxyurea, 98%, powder
Sigma-Aldrich
Caffeine, anhydrous, 99%, FCC, FG
Sigma-Aldrich
Theophylline, anhydrous, ≥99%, powder
Sigma-Aldrich
Acetaminophen, BioXtra, ≥99.0%
Sigma-Aldrich
Erythromycin, BioReagent, suitable for cell culture
Sigma-Aldrich
Amoxicillin, potency: ≥900 μg per mg
Sigma-Aldrich
Cyclosporin A, 98.5-101.5% (on dried basis)
Sigma-Aldrich
Trimethoprim, ≥98% (HPLC)
Sigma-Aldrich
Acetaminophen, meets USP testing specifications, 98.0-102.0%, powder
Supelco
Sulfamethoxazole, analytical standard
Sigma-Aldrich
Levofloxacin, 98.0-102.0% anhydrous basis (HPLC)
Sigma-Aldrich
Caffeine, Sigma Reference Standard, vial of 250 mg
Supelco
Melting point standard 235-237°C, analytical standard
Sigma-Aldrich
Acetaminophen, analytical standard
Sigma-Aldrich
Prednisolone, ≥99%
Sigma-Aldrich
Prednisone, ≥98%
Sigma-Aldrich
Nifedipine, ≥98% (HPLC), powder
Sigma-Aldrich
Dexamethasone, powder, γ-irradiated, BioXtra, suitable for cell culture, ≥80% (HPLC)
Sigma-Aldrich
Ofloxacin, fluoroquinolone antibiotic
Sigma-Aldrich
Tetracycline, 98.0-102.0% (HPLC)
Supelco
Antipyrine, analytical standard