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.

Pharmacokinetics of reduced iso-α-acids in volunteers following clear bottled beer consumption

“…Previous studies have shown some pharmacokinetics of natural IAA in human volunteers [17,18], RIAA and TIAA in animal models [7], and in humans dosed with large amounts of RIAA [8]. However IAA 5 I2 -I2 a -----I2, I4 I2, I4 I2 I2 RIAA 5 the pharmacokinetics of all the reduced IAA in the blood and urine of humans following consumption of beer have not yet been established.…”

“…These preliminary IAA pharmacokinetic studies demonstrated that IAA compounds can be detected and suggests that the structurally similar reduced IAA may also be able to be targeted. Furthermore, there have been toxicity [19] and pharmacokinetic studies investigating reduced IAA, particularly RIAA and TIAA, due to their possible medicinal properties such as weight loss, antidiabetic, anti-carcinogenic and anti-inflammatory [7,8,[20][21][22][23]. Of these, two studies detected RIAA and TIAA in New Zealand white rabbits [7], and one measured RIAA in humans [8], confirming those reduced IAA groups examined were indeed bioavailable.…”

“…Furthermore, there have been toxicity [19] and pharmacokinetic studies investigating reduced IAA, particularly RIAA and TIAA, due to their possible medicinal properties such as weight loss, antidiabetic, anti-carcinogenic and anti-inflammatory [7,8,[20][21][22][23]. Of these, two studies detected RIAA and TIAA in New Zealand white rabbits [7], and one measured RIAA in humans [8], confirming those reduced IAA groups examined were indeed bioavailable. The long-term stabilities of the reduced IAA groups in stored blood recently concluded that they were less susceptible to degradation than the natural IAA, and refrigeration or freezing conditions provided acceptable stability [24].…”

“…1. These photolytic protective properties allows for the use of these products to be commonly used in isolation in unprotected clear glass bottles [2,4,7,8]. However in order to stablise the bitterness of the beer, they may be used also in conjunction with traditional IAA hopping techniques in green bottles that are subject to low levels of light where some photolytic degradation will still occur to the natural IAA [9].…”

Absolute Configuration of Beer′s Bitter Compounds

“…[11][12][13] Claims that beer and the bittering acids found in beer are beneficial when consumed in moderation have accumulated over time, including positive effects on diabetes, [14][15][16] forms of cancer, [17][18][19][20] and inflammation, [21] and even linking reduced iso-a-acid derivatives to weight loss. [22][23][24] Some of these derivatives affect one illness, [21,[25][26][27][28] whereas others, differing only in the configuration of carbon atoms 4 and 5 of the iso-aacids (Scheme 1), are ineffective. [29] In addition, it was discovered that different grades of bitterness can be related to opposite enantiomers of tetrahydro-iso-a-acids.…”