Bioavailability of hop-derived iso-α-acids and reduced derivatives

Abstract

Iso-α-acids (IAA) and their reduced derivatives (dihydro-iso-α-acids (DHIAA) and tetrahydro-iso-α-acids (THIAA)) have been administered to Caco-2 cell monolayers (30, 60, and 120 μM) to investigate epithelial transport, in both absorptive and secretive directions. In addition, 25 mg kg⁻¹ IAA, DHIAA, and THIAA were applied to New Zealand white rabbits (±3–3.5 kg) in a single intravenous and oral dose. The most important pharmacokinetic parameters (C_max, t_max, half life, clearance, and AUC_0−∞) and the absolute bioavailability were determined for each class of hop acid. The results from the in vitro Caco-2 study of IAA, DHIAA, and THIAA, showed a higher membrane permeability for IAA and THIAA, both in absorptive (P_appAB range 1.6–5.6 × 10⁻⁶ cm s⁻¹) and secretive directions (P_appBA range 5.7–16.3 × 10⁻⁶ cm s⁻¹), when compared to DHIAA. Factors limiting transport of DHIAA could include phase II metabolism. After oral and i.v. dosing to New Zealand white rabbits, the absolute bioavailability for IAA was determined to be 13.0%. The reduced derivatives reached higher bioavailabilities with 28.0% for DHIAA and 23.0% for THIAA. The area under curve AUC_0−∞ upon oral gavage for DHIAA and THIAA was 70.7 ± 48.4 μg h ml⁻¹ and 57.4 ± 9.0 μg h ml⁻¹, respectively, while that for IAA was 10.6 ± 5.3 μg h ml⁻¹. Phase I metabolism was indicated as the main factor limiting the bioavailability of IAA. Bioavailability of DHIAA is mostly influenced by phase-II metabolism as shown by enzymatic hydrolysis of plasma samples upon administration of DHIAA.