Conjugative metabolism

The metabolic and pharmacokinetic profile of sucralose (this is a novel intense sweetener with a potency about 600 times that of sucrose) in human volunteers was studied by Roberts and coworkers [82]. Part of this study was realized using PLC in the following chromatographic system in which the stationary phase was silica gel and the mobile phase was ethyl acetate-methanol-water-concentrated ammonia (60 20 10 2, v/v). Separated substances were scraped off separately, suspended in methanol, and analyzed by filtration, scintillation counting, or enzymatic assay. It was shown that the characteristics of sucralose include poor absorption, rapid elimination, limited conjugative metabolism of the fraction absorbed, and lack of bio-accumulative potential. 

With these promoieties, the 3-phenolic hydroxy group of p-estradiol (the normally metabolized functional group) was blocked so that first-pass conjugative metabolism could be reduced. The relative bioavailability of estradiol was significantly improved when administered in these prodrug forms. A 17-fold increase was observed with the estradiol-3-salicylate. The P-estradiol-3-anthrani-late increased the systemic availability five-fold. 

In addition to oxidative and conjugative metabolism, other enzymes are also present in the Caco-2 model, though at lower levels than in the human enterocyte in vivo. These are mainly apical cell surface peptidases, such as aminopeptidases... 

The major metabolic pathways of the TCAs are demethylation, hydroxyla-tion, and glucuronide conjugation. Metabolism of the TCAs appears to be linear within the usual dosage range, but dose-related kinetics cannot be ruled out in the elderly. 

Raloxifene, a more complete uterine antagonist than tamoxifen or clomiphene, significantly reduces leiomyoma size in post-menopausal women [31], yet it is less efficacious at reducing tumor volume in pre-menopausal women [32], This result has been attributed to the poor pharmacokinetic properties of this compound in which extensive conjugative metabolism of the phenol(s) limits the circulating levels of the parent drug. In addition, clinical outcomes in premenopausal women treated with raloxifene suggest that this compound, like tamoxifen and clomiphene, can affect the ovaries via the HPO axis [33]. These data, taken collectively, indicate that current SERMs lack the efficacy, pharmacokinetic, and ovarian safety properties needed to treat leiomyoma in ovulatory women. 

Smith, G., Watkins, J., Thompson, T., Rozman, K. and Klassen, C. (1984). Oxidative and conjugative metabolism of xenobiotics by livers of cattle, sheep, swine and rats. J. Anim. Sci. 58 386-395. 

Thomas, C. et al. (2001) Conjugative metabolism of 1,2-dibromoethane in mitochondria disruption of oxidative phosphorylation and alkylation of mitochondrial DNA. Biochem. Pharmacol., 61 (5), 595-603. 

Ebert B, Seidel A, Lampen A. Identification of BCRP as transporter of benzofa] pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists. Carcinogenesis 2005 26 1754—1763. 

Machida M, Morita Y, Hayashi M, et al. 1982. Pharmacokinetic evidence for the occurrence of extrahepatic conjugative metabolism of p-nitrophenol in rats. Biochem Pharmacol 31 787-791. 

Moldeus P, Vadi H, Berggren M. 1976. Oxidative and conjugative metabolism of p-nitroanisole and p-nitrophenol in isolated rat liver cells. Acta Pharmacol Toxicol 39 17-32. 

Mudd, S.H., 1973. Biochemical mechanisms of methyl trarrsfer. Metabol. Conjugation Metabol. Hydro ., 3 297-350. 

Mizuma, T., Kawashima, K., Sakai, S., Sakaguchi, S. and Hayashi, M. (2005) Differentiation of organ availability by sequential and simultaneous analyses intestinal conjugative metabolism impacts on intestinal availability in humans. Journal of Pharmaceutical Sciences, 94, 571-575. 

Hepatic Effects. Stewart and Andrews (1966) reported a case in which a man survived drinking 1 ounce (600 mg/kg) of 1, 1, 1-trichloroethane. Serum transaminase levels remained within normal limits, but serum bilirubin levels became slightly elevated after 48 hours. Increased serum bilirubin levels may result from reduced biliary excretion (i.e., cholestatic liver damage). Alternatively, hyperbilirubinemia may result from diminished hepatic conjugative metabolism of bilirubin. 

Radwan, E. E. and Ramsdell, J. S., Characterization of in vitro oxidative and conjugative metabolic pathways for hrevetoxin (PbTx-2), Toxicol. Sci. 89, 57, 2006. 

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