Hepatic biotransformation

In a study of the metabolism of methyl parathion in intact and subcellular fractions of isolated rat hepatocytes, a high performance liquid chromatography (HPLC) method has been developed that separates and quantitates methyl parathion and six of its hepatic biotransformation products (Anderson et al. 1992). The six biotransformation products identified are methyl paraoxon, desmethyl parathion, desmethyl paraoxon, 4-nitrophenol, />nitrophenyl glucuronide, and /wiitrophenyl sulfate. This method is not an EPA or other standardized method, and thus it has not been included in Table 7-1. 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

Bhuvaneswari, V., Velmurugan, B., and Nagini, S. 2002. Induction of glutathione-dependent hepatic biotransformation enzymes by lycopene in the hamster cheek pouch carcinogenesis model. J Biochem Mol Biol Biophys 6 257-260. 

Lemaire, P., A. Mathieu, J. Giudicelli, and M. Lafaurie. 1992c. Effect of diet on the responses of hepatic biotransformation enzymes to benzo[a]pyrene in the European sea bass (Dicentrarchus labrax). Comp. Biochem. Physiol. 102C 413-420. 

Juchau, M.R. Hepatic biotransformation of environmental xenobiotics in six strains of rainbow trout (Satmo gairdneri) J. Fish Res. Board Can. (1976) 33, 666—675 ... 

Chaturvedi et al. (1991) studied the effects of mixtures of parathion, toxaphene, and/or 2,4-D on the hepatic mixed-function oxygenase in ICR male mice. They found that a 7-day toxaphene pretreatment enhanced the hepatic biotransformation of parathion and its metabohte paraoxon, both in the presence and absence of NADP. However, in the absence of NADP the enhancement was minor. The authors suggested that toxaphene induced the metabohc pathways of parathion and paraoxon involving the mixed-function oxygenase and that paraoxonase is not involved in the... 

Sevoflurane undergoes hepatic biotransformation (about 3% of the inhaled dose), and it is somewhat degraded by conventional CO2 absorbents. The degradation product from the absorbent has been reported to be nephrotoxic, although the report is controversial and not substantiated by more recent studies. Sevoflurane s actions on skeletal muscle and on vascular regulation within the CNS are similar to those described for the other halogenated hydrocarbon anesthetics. 

Dorough. Effects of cigarette smoke and dietary vitamin E levels on selected lung and hepatic biotransformation enzymes in mice. Drug Nutr Interact 1985 3(4) 213-222. 

Patel, J.M., Gordon, W.P, Nelson, S.D. Leibman, K.C. (1983) Comparison of hepatic biotransformation and toxicity of ahyl alcohol and [l,l-2H2]allyl alcohol in rats. DrugMetab. Dispos., 11, 164-166... 

Once first-pass metabolism has occurred, metabolites are excreted into the bile and then the small bowel. Those that are lipid soluble are reabsorbed into the portal circulation, eventually entering the systemic circulation. These metabolites may have a similar or substantially different pharmacological profile from their parent drug. For example, chlorpromazine undergoes extensive hepatic biotransformation and has 168 theoretical metabolites, 70 of which have been identified in plasma and... 

The nature of the configuration is the basis upon which local anaesthetics are classified. Ester local anaesthetics are characteristically unstable compounds that are broken down in the plasma by plasma cholinesterases. In contrast, the amide agents are very stable compounds that require extensive hepatic biotransformation. The more complex the linkage, the greater the tendency for toxicity. 

The ability of liver to biotransform chloramphenicol has been also demonstrated in several fish species. In pertinent studies, various metabolic pathways were determined and chloramphenicol-glucuronide, chloramphenicol-base, chloramphenicol-alcohol, and chloramphenicol-oxamate were the main metabolites observed (34, 35). Following hepatic biotransformation, a large proportion of the administered dose was excreted in the urine. 

Singh A, Singh SP, Bamezai R. 1995. Postnatal modulation of hepatic biotransformation system enzymes via translactational exposure of FI mouse pups to turmeric and curcumin. Cancer Lett 96 87-93. 

Increased clearance of steroid hormones due to induction of hepatic biotransformation enzymes following chemical exposure often has been cited as a possible mechanism by which toxicants could lower circulating testosterone or 17/3-estradiol levels. While enhanced clearance of sex steroids has been demonstrated following chemical exposure and induction of hepatic biotransformation enzymes, elegant feedback control mechanisms tend to ensure that more hormone is produced and homeostasis is maintained (Figure 17.2). Enhanced clearance of sex steroids can contribute to endocrine disruption if the toxicity also results in impaired hormone synthesis (i.e., gonadal toxicity or interference with the feedback control of hormone synthesis). 2,3,7,8-Tetrachlorodibenzodioxin appears to lower circulating sex steroid levels via this dual effect. 

Atenolol is characterized by a low hepatic clearance for the most part of body clearance is extrahepatic.(18) The hepatic biotransformation of atenolol gives rise to the pharmaceutically inactive catabolites, such as compound hydroxylated at the methylene group attached to the benzene ring, and compounds conjugated with glucuronic acid.(7 ... 

These resemble the penicillins structurally, in mode of action and in general lack of toxicity. They are primarily excreted by the kidney by tubular secretion and some also by glomerular filtration (e.g. cephalothin) or only by glomerular filtration (e.g. cefazolin). Cefoperazone is excreted by the bile. Cefotaxime undergoes hepatic biotransformation to active metabolites. Hypersensitivity reactions are qualitatively similar to those of the penicillins, but the epileptogenic potential is less. 

The quantitatively most significant second-phase reaction of hepatic biotransformation is glucuronidation that takes place in the ER. The transfer of glucuronosyl group from... 

Some of the greatest differences in the pharmacokinetics of stereoisomers can be attributed to stereoselective hepatic biotransformation. The oral clearance of 5-mephenytoin is 170 times that of the R enantiomer in extensive metabolizers of the drug. ° This large difference in clearance is reflected in a 2-h half-life for the 5-mephenytoin compared to a 76-h half-life for the R enantiomer in the same patient group. Interestingly, the half-life of the S isomer (63 h) and the R isomer (77 h) are similar in poor metabolizers of mephenytoin. Numerous other examples of stereoselectivity in hepatic clearance can be found in the literature. ... 

As with the situation in mammals, wide variations exist among avian species in the half-life of drugs that are primarily eliminated by hepatic biotransformation.The half-life of antimicrobial agents is prolonged in poikilothermic species (fish and reptiles), which is consistent with their much lower metabolic turnover rate, and is influenced by ambient (in the case of fish, water) temperature (Table 12). The rate of drug elimination increases (i.e., half-life decreases) with increase in ambient temperature and varies among fish species. 

Species variations in the half-life of drugs that are eliminated by renal excretion is less pronounced than for lipid-soluble drugs that undergo extensive hepatic biotransformation. The half-life of gentamicin, which is eliminated solely by glomerular filtration, is 0.5-1 h in laboratory animals, 1.25-2.5 h in domestic animals. 

The phenothiazines undergo hepatic biotransformation (Dewey et al 1981). The primary metabolites are glucuronide conjugates of the parent drug. Acepromazine and promazine both produce a number of metabolites that are detectable in the urine of the horse. Since the duration of effect often exceeds the detection of the phenothiazine in plasma, it is possible that some metabolites retain pharmacological activity (Marroum et al 1994). Phenothiazines should be used with caution in horses with impaired liver function because of the potential for marked prolongation of effect. 

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