Metabolism, 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. 

Hepatic mixed-function oxidase activities demonstrated seasonal trends, with higher specific activities in the cold weather months in both populations with few differences in enzyme activities or cytochrome levels between the two populations. Metabolism of aldrin, dieldrin and DDT was similar between the two populations. R fish have larger relative liver size and, therefore, a greater potential for xenobiotic metabolism. However, biotransformation appears to be of minor importance in chlorinated alicyclic insecticide resistance in mosquitofish barriers to penetration appear to be of greater importance and an implied target site insensitivity appears to be the most important factor in resistance. 

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 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. 

This biotransformation process takes place principally in the liver, i.e. in the smooth endoplasmic reticulum, partly also in the mitochondria. The kidneys, lungs, intestine, muscles, spleen and skin are involved to a lesser degree in biotransformation. Through hydrolysis and reduction, the intestinal flora may also play a role in this metabolic process. Biotransformation is limited by the hepatic blood flow (= flow-limited elimination) and by the capacity of microsomal enzyme systems (= capacity-limited elimination). (80, 95)... 

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. 

Albendazole and fenbendazole, prochiral sulphide benzimidazole anthelmintics, are metabolically converted (sulphoxidation) to the corresponding active sulphoxide metabolites, each of which exists in the plasma as two enantiomers. Sulphoxide benzimidazoles have a chiral centre around the sulphur atom in their molecules. The sulphoxide metabolites (enantiomers) are irreversibly metabolized (sulphonation) to inactive sulphones. This pathway of hepatic biotransformation has been shown to occur both in ruminant (sheep, goats, cattle) and monogastric (man, dogs, rats) species (Delatour et al., 1991b,... 

IMPAIRED HEPATIC CLEARANCE OF DRUGS The effect of liver disease on the hepatic biotransformation of drugs cannot be predicted from any measure of hepatic function. Thus, even though the metabolism of some drugs is decreased with impaired hepatic function, there is no quantitative basis for dose adjustment other than assessment of the clinical response and plasma concentration. The oral bioavailability of drugs with extensive first-pass hepatic clearance (e.g., morphine, meperidine, midazolam, and nifedipine) may be increased in liver disease. 

Aluminum salts, cholestyramine, and colestipol may decrease absorption of /3 blockers. Pheny-toin, rifampin, and phenobarbital, as well as smoking, induce hepatic biotransformation enzymes and may decrease plasma concentrations of /3 receptor antagonists that are metabolized extensively (e.g., propranolol). Cimetidine and hydralazine may increase bioavailability of propranolol and metoprolol by affecting hepatic blood flow, fi Receptor antagonists can impair the clearance o/lidocaine. 

Reboxetine has a complex hepatic biotransformation in humans, including hydroxylation, 0-dealkylation, and oxidation, followed by glucuronidation and sulfoconjugation. In vitro hepatic experiments have indicated that CYP3A4 is the major enzyme responsible for the metabolism of reboxetine. 

Elimination covers both excretion (i.e. disappearance of unchanged drug from the body) and biotransformation (metabolism). Some dmgs are excreted in the bile and may be eliminated with the faeces, others are excreted in saliva. General anaesthestics are often excreted by the lungs. However, renal excretion and hepatic biotransformation are the major routes of dmg elimination and these processes will be discussed, together with biliary excretion. 

Valproic acid In addition to competing for phenytoin plasma protein binding sites, valproic acid inhibits the metabolism of phenytoin, phenobarbital, and lamotrigine. Hepatic biotransformation of valproic acid leads to formation of a toxic metabolite that has been implicated in the hepatotoxicity of the drug. 

Studies on metabolic stability using hepatocyte suspensions are not feasible for automation/HTS, but these studies do provide rather complete profiles of hepatic biotransformation without the supplements of cofactors and cosubstrates. The use of S9 in metabolic stability studies can be evaluated in a manner similar to that used for the microsomal assays, but with the possible addition of a broader panel of cofactors or cosubstrates. These include NADPH for CYP/FMO-mediated reactions, NADH for xanthine oxidoreductase and quinone oxidoreductase 2, NADPH-dependent reductions by carbonyl reductases, and NADPH/NADH-dependent reductions catalyzed by aldo-keto reductases, uridine 5 -diphosphate... 

Ephedrine undergoes hepatic biotransformation being excreted mostly unchanged in urine [83]. From 8 % to 20 % of ephedrine is excreted after demethylation and delamination according to its metabolism showed in Scheme 38.3. 

The species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance of esfenvalerate and deltamethrin using rat and human liver microsomes were examined [33]. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The CLint of esfenvalerate was estimated to be threefold greater in rodents than in humans on a per kg body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes however, in human liver microsomes, deltamethrin was eliminated almost entirely via... 

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