title: In vitro disposition profiling of heterocyclic compounds.
abstract: Compound libraries that are screened for biological activity commonly contain heterocycles. Besides potency, drug-like properties need to be evaluated to ensure in vivo efficacy of test compounds. In this context, we determined hepatic and intestinal disposition profiles for 17 heterocyclic compounds. All studied compounds showed rapid uptake in suspended rat hepatocytes, whereas metabolism was poor and the rate-limiting step in hepatic elimination. In vitro assays demonstrated a relatively low solubility and high intestinal permeability. Based on these in vitro data, heterocycles were categorized in the biopharmaceutics classification system (BCS) and the biopharmaceutics drug disposition classification system (BDDCS) to predict disposition characteristics before clinical data are available. Our findings emphasized the importance to use hepatocytes in addition to microsomes to study metabolism, since the latter lack non-microsomal enzymes and cellular context. Moreover, intracellular exposure should be considered to gain insight in the relevant fraction of the compound available at the enzymatic site. Finally, the study reveals discrepancies associated with the classification of heterocycles in BCS versus BDDCS. These probably originate from the binary character of both systems.
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Janneke
authors.initials: J
authors.lastname: Keemink
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wuyts
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Nicolaï
authors.affiliation: Laboratory for Medicinal Chemistry, Rega Institute, KU Leuven, Belgium; Interface Valorisation Platform (IVAP), Laboratory of Medicinal Chemistry, KU Leuven, Belgium.
authors.forename: Steven De
authors.initials: SD
authors.lastname: Jonghe
authors.affiliation: Laboratory for Medicinal Chemistry, Rega Institute, KU Leuven, Belgium.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Stella
authors.affiliation: Laboratory for Medicinal Chemistry, Rega Institute, KU Leuven, Belgium.
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium. Electronic address: Pieter.annaert@pharm.kuleuven.be.
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
mesh_terms: D000818:Animals; D001702:Biopharmaceutics / Q000379:methods; D055808:Drug Discovery; D022781:Hepatocytes / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
chemical_list: D006571:Heterocyclic Compounds
keywords: ADMET; Biopharmaceutics drug disposition classification system (BDDCS); Hepatic drug disposition; Heterocycles; Intestinal drug disposition