First-Pass Metabolism via UDP-Glucuronosyltransferase: a Barrier to Oral Bioavailability of Phenolics

Abstract

Glucuronidation mediated by UDP-glucuronosyltransferases (UGTs) is a significant metabolic pathway that facilitates efficient elimination of numerous endo- and xenobiotics including phenolics. UGT genetic deficiency and polymorphisms or inhibition of glucuronidation by concomitant use of drugs are associated with inherited physiological disorders or drug induced toxicities. Moreover, extensive glucuronidation can be a barrier to oral bioavailability as the first-pass glucuronidation (or premature clearance by UGTs) of orally administered agents usually results in the poor oral bioavailability and lack of efficacies. This review focused on the first-pass glucuronidation of phenolics including natural polyphenols and pharmaceuticals. The complexity of UGT-mediated metabolism of phenolics is highlighted with species-, gender-, organ- and isoform-dependent specificity, as well as functional compensation between UGT1A and 2B subfamily. In addition, recent advances are discussed with respect to the mechanisms of enzymatic actions including the important properties such as binding pocket size and phosphorylation requirements.

Non-digestible stachyose promotes bioavailability of genistein through inhibiting intestinal degradation and first-pass metabolism of genistein in mice

“…The phase II enzymes UGT and SULT are significant metabolic pathways for numerous endo- and xeno-biotics in the enterocytes, which are also known to interact with the ingested flavonoids and accelerate efflux transportation of flavonoids to reduce bioavailability of flavonoids [12, 22]. As shown in Figure 4(a, b), treatment of stachyose alone was able to inhibit the expression of small intestinal UGT and SULT, respectively ( p <0.05), while treatment of individual genistein caused a severe rise in UGT and SULT, compared to that in the control mice, respectively ( p <0.05).…”

“…It is interesting to note that flavonoids easily undergo first-pass metabolism catalyzed by intestinal and hepatic phase II metabolic enzymes, leading to low bioavailability of flavonoids [12,13]. In addition, it was reported that long-term treatment of genistein could induce the related protein expression of first-pass metabolism in mice [14,15] and the activities of phase II metabolic enzymes in mice could be mediated by oligosaccharides [13,16,17].…”

Glucuronidation of OTS167 in Humans Is Catalyzed by UDP-Glucuronosyltransferases UGT1A1, UGT1A3, UGT1A8, and UGT1A10

“…We demonstrated that UGT1A1 and UGT1A3 are the major hepatic UGTs involved in OTS167 metabolism. Among these, UGT1A1 appears to play the main role based on our experimental data and its high level of hepatic and intestinal expression (Nakamura et al, 2008;Izukawa et al, 2009;Ohno and Nakajin, 2009;Wu et al, 2011;Court et al, 2012;Harbourt et al, 2012;Rowland et al, 2013). Supporting data include high CL int Fig.…”

Is there a paradigm shift in use of microsomes and hepatocytes in drug discovery and development?

“…In general, the experimental conditions utilizing microsomes can be easily controlled in comparison to in vivo and in situ models. Moreover, these methods are theoretically applicable to all species and can be used to study phase I and phase II drug metabolism to get the enzyme isoforms activity profile [7,8]. There are few limitations of microsomes, for instance, they have to be supplied with co-factors like NADPH, or UDPGA for the metabolic reactions to initiate, and lack the cell membranes to mimic the physiological environment in hepatocytes [7,8].…”

“…Moreover, these methods are theoretically applicable to all species and can be used to study phase I and phase II drug metabolism to get the enzyme isoforms activity profile [7,8]. There are few limitations of microsomes, for instance, they have to be supplied with co-factors like NADPH, or UDPGA for the metabolic reactions to initiate, and lack the cell membranes to mimic the physiological environment in hepatocytes [7,8]. In addition, it suffers from its non-physiological nature due to the absence of cellular metabolism, membrane transport and production of co-factor [3,9].…”