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.

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Rowland A, Knights KM, Mackenzie PI, Miners JO

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.

Drug Metab Dispos. 2009 Jul;37(7):1395-403. doi: 10.1124/dmd.109.027656. Epub 2009 Apr 27.

PubMed ID
19398502 [ View in PubMed
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Abstract

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 K(d) values similar to those reported for rat IFABP. Basic drugs bound negligibly to IFABP. Based on fraction unbound (f(u)) at a protein concentration of 0.5% (w/v), binding of acidic and neutral drugs ranged from minor (f(u) > 0.8) to moderate (f(u) 0.5-0.8). Of the compounds screened, highest binding to IFABP was observed for sulfinpyrazone (an acid) and beta-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 K(m) 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.

DrugBank Data that Cites this Article

Drug Carriers
DrugCarrierKindOrganismPharmacological ActionActions
Arachidonic AcidFatty acid-binding protein, intestinalProteinHumans
No
Not AvailableDetails
EstradiolFatty acid-binding protein, intestinalProteinHumans
No
Binder
Details
Estradiol acetateFatty acid-binding protein, intestinalProteinHumans
No
Not AvailableDetails
Estradiol benzoateFatty acid-binding protein, intestinalProteinHumans
No
Not AvailableDetails
Estradiol cypionateFatty acid-binding protein, intestinalProteinHumans
No
Not AvailableDetails
Estradiol dienanthateFatty acid-binding protein, intestinalProteinHumans
No
Not AvailableDetails
Estradiol valerateFatty acid-binding protein, intestinalProteinHumans
No
Not AvailableDetails
SulfinpyrazoneFatty acid-binding protein, intestinalProteinHumans
No
Not AvailableDetails