Chloramphenicol
Thomas T. Yoshikawa, Shobita Rajagopalan in Antibiotic Therapy for Geriatric Patients, 2005
Chloramphenicol is metabolized primarily by the liver. In the liver it is conjugated with glucuronic acid and excreted in this inactive form by the kidney. Aging-related changes in liver function may alter the metabolism of this drug. Only about 5-10% of the administered dose is recovered in the urine as biologically active chloramphenicol. Nonetheless, in the absence of renal disease, concentrations of 150-200 pg/mL of active drug are achieved, which is sufficient to treat urinary tract infections if necessary. In patients with renal failure, chloramphenicol urinary concentrations are markedly reduced (15). Dose adjustment is not routinely necessary in elderly patients with mild or moderate renal dysfunction. Neither peritoneal infusion nor hemodialysis alters serum levels sufficientiy to necessitate dose modifications (13,16).
In Vitro to In Vivo Extrapolation of Metabolic Rate Constants for Physiologically Based Pharmacokinetic Models
John C. Lipscomb, Edward V. Ohanian in Toxicokinetics and Risk Assessment, 2016
Glucuronosyl transferases are a family of enzymes that catalyze the transfer of glucuronic acid from uridine diphospho (UDP)-glucuronic acid to acceptor molecules containing hydroxyl, phenol, carboxylic acid, thiol, or amine groups (45,46). Kinetic studies have shown that these enzymes follow a random sequential mechanism. Glucuronosyl transferases are located in the endoplasmic reticulum, and their biosynthesis can be induced by a number of drugs and xenobiotics. Some forms of glucuronosyl transferases are coordinately induced with CYP. Conjugation with glucuronic acid makes lipophilic molecules much more water soluble and readily excretable and therefore is considered a detoxication pathway. However, acyl glucuronides can undergo structural rearrangements and react with nucleophilic groups in cells (47,48). Thus, glucuronidation of some molecules may represent bioactivation. For example, the acyl glucuronide of the hypolipidemic drug clofibrate acylates cellular macromolecules (47). However, the toxicological significance of this reaction is unclear.
Glycosaminoglycans
Luke R. Bucci in Nutrition Applied to Injury Rehabilitation and Sports Medicine, 2020
Hyaluronan (as a high-molecular-weight species of 2 million Da.) exhibited inhibitory effects on in vitro cartilage degradation by activated neutrophils at levels >1.0 mg/ml.1245 HA may also prevent attachment of inflammatory mediators or immune complexes to immune and synovial cell receptors, thus limiting inflammatory responses.1246 HA binds acute phase reactant proteins in synovial fluid of rheumatoid arthritis subjects, which may further aid HA in resisting degradation from free radicals.1247 HA, and one of its two components, d-glucuronic acid, possess antioxidant activity against free radicals formed by activated neutrophils.1246 Thus, native hyaluronan possesses other properties that promote joint health in addition to viscoelastic properties. Table 3 lists some proposed mechanisms of action for the use of hyaluronan in connective tissue healing.
Glucuronidation of icaritin by human liver microsomes, human intestine microsomes and expressed UDP-glucuronosyltransferase enzymes: identification of UGT1A3, 1A9 and 2B7 as the main contributing enzymes
Published in Xenobiotica, 2018
Li Wang, Xiaodan Hong, Zhihong Yao, Yi Dai, Guoping Zhao, Zifei Qin, Baojian Wu, Frank J. Gonzalez, Xinsheng Yao
Glucuronidation is one of the most significant phase II conjugation reactions (Wu et al., 2011). Generally, it is a detoxification mechanism because the glucuronide is usually pharmacologically inactive and rapidly eliminated from the body due to its highly polar nature (Ritter, 2000). Meanwhile, it accounts for the clearance of ∼35% drugs metabolized by phase II enzymes (Evans & Relling, 1999). The mechanism of glucuronidation reaction is that a glucuronic acid derived from the cofactor uridine diphosphoglucuronic acid (UDPGA) is transferred to the substrate, generating the glucuronidated metabolite (or glucuronide) via the action of the UDP-glucuronosyltransferase enzymes (UGTs) (Sun et al., 2015). Human UGT enzymes are systematically classified into four subfamilies, UGT1, UGT2, UGT3 and UGT8 (Mackenzie et al., 2005). Usually, the UGT1A and 2B enzymes contribute significantly to metabolism and detoxification of xenobiotics (Lu et al., 2016). The UGT1A family contains nine members (i.e. UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10), whereas the UGT2B family contains seven members (i.e. UGT2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28).
An integrated analytical strategy to decipher the metabolic profile of alkaloids in Compound Kushen injection based on UHPLC-ESI-QTOF/MSE
Published in Xenobiotica, 2023
Li Zhang, Ruijuan Li, Ting Zheng, Huan Wu, Yanyan Yin
M21 eluted at 4.29 min with the m/z of 441.2234 [M + H]+, which was 192 Da heavier than the m/z of lupanine, and the tR of M21 shorter than lupanine. We hypothesised that M21 is a metabolite of lupanine which underwent oxidation (+16 Da) and glucuronidation (+176 Da). The hypothesis was tested through the exact mass of the secondary fragment ions produced by 441.2234 [M + H]+. The high-resolution mass spectrogram under high-energy collision is shown in Figure S5. The fragment ion at m/z 265.1912 may be formed by 441.2234 directly removing glucuronic acid (−C6H8O6). Another fragment ion m/z 263.1759 had the highest abundance formed by 441.2234 directly removing C6H10O6. m/z 245.1658 is a fragment ion produced by the dehydration of 263.1759, which can further cleavage yield four fragment ions (205.1339 (−C3H4), 203.1198 (−C3H6), 191.1191 (−C4H6), and 150.1281 (−C5H5NO)). Among these fragment ions, m/z 150.1281 can further remove C2H4 to form m/z 122.0977. Owing to this, M21 was considered an oxidation and glucuronidation metabolite of lupanine. The other 9 lupanine-related metabolites were characterised by a similar method.
Wogonin glucuronidation in liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice
Published in Xenobiotica, 2020
Nobumitsu Hanioka, Takashi Isobe, Toshiko Tanaka-Kagawa, Susumu Ohkawara
Wogonin (≥98%) was purchased from MedChemExpress (Monmouth Junction, NJ, USA). Wogonin 7-glucuronide (≥98%) was purchased from LKT Laboratories (St. Paul, MN, USA). Formononetin (≥98%) was obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Alamethicin was purchased from Sigma-Aldrich (St. Louis, MO, USA). UDP-glucuronic acid was obtained from Nacalai Tesque (Kyoto, Japan). Pooled microsomes of human livers (race, Caucasian and Hispanic; age, 20–78 years old), human intestines (race, Caucasian and Hispanic; age, 18–55 years old), monkey livers (strain, cynomolgus; age, 3–8 years old), monkey intestines (strain, cynomolgus; age, 2–5 years old), dog livers (strain, beagle; age, 0.5–3 years old), dog intestines (strain, beagle; age, >6 months old), rat livers and intestines (strain, Sprague–Dawley; age, >8 weeks old), and mouse livers and intestines (strain, CD1; age, >11 weeks old) were obtained from Sekisui XenoTech (Lenexa, KS, USA). All other chemicals and reagents used were of the highest quality commercially available.
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