Renal Drug-Metabolizing Enzymes in Experimental Animals and Humans
Robin S. Goldstein in Mechanisms of Injury in Renal Disease and Toxicity, 2020
The contribution of the kidney to in vivo glucuronidation of various compounds has been elucidated by the elegant specific activity difference ratio technique, in which radiolabeled substrate and unlabeled glucuronide are continuously infused into the general circulation (see Tremaine et al., 1985, for a review). Using this technique, Rush et al. (1983c) and Tremaine et al. (1984) concluded that rat kidney contributed about 10% of the total body glucuronidation of 4-nitrophenol in the male and 20% in the female rat. The sex difference was due to differences in UDPGT activities in the kidney with this substrate, which did not exist for the glucuronidation of morphine. A similar high renal contribution to the conjugation of 1-naphthol in vivo was found in the rat. In other species it is known that the kidney contributes significantly to the in vivo conjugation of morphine, for example, in the dog (Gerkens et al., 1981; Jacqz et al., 1986), sheep (Sloan et al., 1991), and man (Mazoit et al., 1987). The kidney also contributes to the extrahepatic metabolism of this opiate during the anhepatic phase of patients undergoing liver transplantation (Bodenham et al., 1989).
Clinical pharmacology: traditional NSAIDs and selective COX-2 inhibitors
Pamela E Macintyre, Suellen M Walker, David J Rowbotham in Clinical Pain Management, 2008
NSAIDs that are metabolized to inactive acyl glucuronides (e.g. ketoprofen, diflunisal, indometacin (indomethacin), naproxen) are normally eliminated by the kidney.6, 8, 9, 10 However, a reduction in renal function can result in accumulation of these conjugates leading to a “futile cycle” in which the glucuronide metabolites are hydrolyzed in the vascular compartment back to active drug.11 This reactivation is especially important in the elderly, in whom reduced renal function can lead to increased levels of glucuronides.9 The renal excretion of unmetabolized NSAID is generally not a major pathway of elimination (even when the urine is alkaline), except for azapropazone (apazone), and salicylates. Small increases in urinary pH that can occur with antacid therapy can significantly lower the plasma concentrations of salicylates.
Xenobiotic Biotransformation
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
Reactions catalyzed by glucuronyltransferases [EC 2.8.2.1.; see reviews by Bock et al. (1986) and Bock and Schirmer (1987)] are both qualitatively and quantatively the most important phase II biotransformation reactions due to the broad range and chemical diversity of substrates. UDP-glucuronic acid is the co-factor for these enzymes. The transferases catalyze the translocation of glucuronic acid from UDP-glucuronic acid to an appropriate receptor to form the β-d-glucuronide. The enzyme location is predominately microsomal. Activity is highest in the liver; measurable activities are present also in kidney, intestine, skin, brain, and spleen. Substrates are aliphatic alcohols and carboxylic acids (converted to O-glucuronides), primary and secondary aromatic and aliphatic amines (conjugated to N-glucuronides), free sulfydryl-containing compounds (conjugated to S-glucuronides), and compounds containing nucleophilic carbon atoms (conjugated to C-glucuronides). Glucuronidation contributes a carboxyl group, which exists primarily in ionized form at physiologic pH. This ionized carboxyl group promotes excretion by increasing the xenobiotic’s water solubility and substrate affinities for transport by biliary and renal organic anion systems.
Microbial biotransformation – an important tool for the study of drug metabolism
Published in Xenobiotica, 2019
Rhys Salter, Douglas C. Beshore, Steven L. Colletti, Liam Evans, Yong Gong, Roy Helmy, Yong Liu, Cheri M. Maciolek, Gary Martin, Natasa Pajkovic, Richard Phipps, James Small, Jonathan Steele, Ronald de Vries, Headley Williams, Iain J. Martin
The selection of compound (7a) as a preclinical candidate required understanding of the pathways contributing to the compound’s clearance. UGT-mediated glucuronidation was observed as a primary pathway with the potential for this to occur either at the alcohol functionality (ether glucuronide) or at the carboxylic acid (acyl glucuronide). Consequently, studies were being performed to assess the formation of an unstable acyl glucuronide due to concerns over the potential link to drug-induced liver injury of this type of metabolite (Lassila et al., 2015; Sawamura et al., 2010). These various investigations, including testing the stability of the glucuronides, required the preparation and isolation of both glucuronide species. Although the chemical synthesis of the acyl glucuronide was facile, the tertiary alcohol was refractory to ether glucuronide generation, presumably due to steric hindrance. Microbial synthesis was successful in generating both glucuronides.
Metabolism and disposition of corylifol A from Psoralea corylifolia: metabolite mapping, isozyme contribution, species differences and identification of efflux transporters for corylifol A-O-glucuronide in HeLa1A1 cells
Published in Xenobiotica, 2020
Yang Li, Jinjin Xu, Chunxia Xu, Zifei Qin, Shishi Li, Liufang Hu, Zhihong Yao, Frank J. Gonzalez, Xinsheng Yao
In this study, glucuronidation was the most efficient reaction of CA (Figure 2). Traditionally, the glucuronidation pathway involved at least two distinct and sequential processes, namely, glucuronide formation and excretion (Qin et al., 2018a; Zhang et al., 2015). The glucuronide formation process referred to the cellular production of glucuronides by UGT enzymes, while their transport from intracellular to extracellular compartments required the aids of efflux transporters. This phenomenon also created the interplay between UGT enzymes and efflux transporters (Qin et al., 2018a; Zhang et al., 2015). It was noted that glucuronide excretion (or production) was not always determined by UGT metabolism alone, and efflux transport occasionally could be the rate-limiting step governing the overall efficiency of glucuronidation in vivo (Jeong et al., 2005; Liu and Hu, 2007). In addition, it was widely accepted that the interplay between UGT enzymes and transporters facilitated the production and excretion of glucuronides in the intestine and liver, limiting the oral bioavailability of drugs (Qin et al., 2018a; Zhang et al., 2015). Meanwhile, our previous study have suggested BCRP and MRPs involved in efflux excretion of glucuronide conjugates in HeLa1A1 cells (Qin et al., 2018a). Our data suggested that MRP4 and BCRP as important determinants to disposition of CA in vivo (Figures 5 and 6).
Identification of UGTs and BCRP as potential pharmacokinetic determinants of the natural flavonoid alpinetin
Published in Xenobiotica, 2019
Chunli Qi, Jiangnan Fu, Huinan Zhao, Huijie Xing, Dong Dong, Baojian Wu
Our finding that the BCRP pump mediated efflux transport of alpinetin glucuronide is consistent with previous studies in which BCRP was involved in the excretion of many flavonoid glucuronides (Liu et al., 2006; Xu et al., 2009; Zhou et al., 2011). Another finding that inhibition of BCRP led to down-regulation of cellular glucuronidation (Figure 6) lend a strong support to the kinetic interplay between UGTs and efflux transporters as noted previously (Zhang et al., 2015). The possible mechanism for the occurrence of this kinetic interplay was proposed. Inhibition of BCRP results in reduced glucuronide excretion, leading to marked accumulation of glucuronide within the cells. Intracellular glucuronide accumulation activates the deglucuronidation pathway (mediated by β-glucuronidase (Sun et al., 2015), thereby facilitating conversion of glucuronide back to the parent compound and reducing the total cellular glucuronidation. It was noteworthy that we performed experiments to confirm that the transporter inhibitor Ko143 did not influence the enzyme activity and to ensure the inhibitor was appropriately used (Figure 5). This is necessary because in a previous study the transporter inhibitor has the potential to alter UGT activity as well (Quan et al., 2015).
Related Knowledge Centers
- Glucuronic Acid
- Glucuronidation
- Glycosidic Bond
- Quercetin
- Glycoside
- Kidney
- Morphine-6-Glucuronide
- Scutellarin