RT Journal Article
SR Electronic
T1 Characterization of the Binding of Drugs to Human Intestinal Fatty Acid Binding Protein (IFABP): Potential Role of IFABP as an Alternative to Albumin for in Vitro-in Vivo Extrapolation of Drug Kinetic Parameters
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1395
OP 1403
DO 10.1124/dmd.109.027656
VO 37
IS 7
A1 Rowland, Andrew
A1 Knights, Kathleen M.
A1 Mackenzie, Peter I.
A1 Miners, John O.
YR 2009
UL http://dmd.aspetjournals.org/content/37/7/1395.abstract
AB This work characterized for the first time the binding of acidic, neutral, and basic drugs to human intestinal fatty acid binding protein (IFABP) and, for comparison, to bovine serum albumin (BSA). In addition, the study investigated whether IFABP can substitute for BSA as a constituent in incubations of human liver microsomes (HLMs) in in vitro-in vivo extrapolation (IV-IVE) studies. Each molecule of purified IFABP bound a single molecule of the fluorescent probe 1-anilino-8-naphthalene sulfonate or arachidonic acid with Kd values similar to those reported for rat IFABP. Basic drugs bound negligibly to IFABP. Based on fraction unbound (fu) at a protein concentration of 0.5% (w/v), binding of acidic and neutral drugs ranged from minor (fu > 0.8) to moderate (fu 0.5–0.8). Of the compounds screened, highest binding to IFABP was observed for sulfinpyrazone (an acid) and β-estradiol (a neutral compound). However, binding to IFABP was lower than to BSA for all the drugs investigated. To determine the potential suitability of IFABP as an alternative to BSA for enhancing the prediction accuracy of IV-IVE based on human liver microsomal kinetic data, the kinetics of zidovudine (AZT) glucuronidation by HLM were characterized in the absence and presence of BSA and IFABP (0.5–2.5%, w/v). Each protein reduced the Km for AZT glucuronidation in a concentration-dependent manner, although a higher content of IFABP in incubations (2.5 versus 1–1.5% for BSA) was necessary for a 10-fold reduction in this parameter. The results indicate that IFABP is likely to have advantages over BSA in microsomal kinetic studies with drugs that bind extensively to albumin.