Hydrolysis reactions hepatic

Natural (-)-cocaine (7.57, Fig. 7.8), which has the (2/ ,3S)-configuration, is a relatively poor substrate for hepatic carboxylesterases and plasma cholinesterase (EC 3.1.1.8), and also a potent competitive inhibitor of the latter enzyme [116][121], In contrast, the unnatural enantiomer, (+)-(2S,3/ )-cocaine, is a good substrate for carboxylesterases and cholinesterase. Because hydrolysis is a route of detoxification for cocaine and its stereoisomers, such metabolic differences have a major import on their monooxygenase-catalyzed toxification, a reaction of particular effectiveness for (-)-cocaine. 

The pharmacokinetic implications of these findings are not straightforward. One important factor that must also be considered is hepatic extraction, which is higher for lovastatin than for its hydroxy acid metabolite [188], Some lactones are useful prodrugs of HMG-CoA reductase inhibitors due to this organ selectivity coupled with the efficiency of enzymatic hydrolysis. However, other factors may also influence the therapeutic response, in particular the extent and rate of metabolic reactions that compete with or follow hydrolysis, e.g., cytochrome P450 catalyzed oxidations, /3-oxidation, and tau-... 

Gastric distress (nausea and vomiting) is one of the most frequently reported adverse reactions. Bladder irritation (e.g., dysuria, polyuria, hematuria, and urgency) may occur. The mandelic salt can crystallize in urine if there is inadequate urine flow and should not be given to patients with renal failure. Patients with preexisting hepatic insufficiency may develop acute hepatic failure due to the small quantities of ammonia formed during methenamine hydrolysis. 

The liver is the principal site of drug metabolism. Hepatic drug metabolism is usually classified into two distinct phases. Phase I reactions are oxidation, reduction or hydrolysis. One of the most important systems that catalyse oxidation are the haem-containing cytochrome P-450 enzymes. 

These are generally metabolised in the hepatic endoplasmic reticulum, the initial reaction being N-dealkylation, with subsequent hydrolysis. An exception to this is prilocaine, where the initial step is hydrolysis, forming o-toluidine. This is further metabolised to 4- and 6-hydro toluidine. The latter is believed to be responsible for the methaemoglobinaemia which may follow high doses. The amidelinked local anaesthetics are extensively protein-bound (between 55% and 95%) particularly to ol-acid glycoprotein. 

Metabolites that are less reactive than suicide inhibitors may impact more distant enzymes, within the same cell, adjacent cells, or even in other tissues and organs, far removed from the original site of primary metabolism. For example, organopho-sphates (OPs), an ingredient in many pesticides, are metabolized by hepatic CYPs to intermediates, which, when transported to the nervous system, inhibit esterases that are critical for neural function. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the ester bond in the neurotransmitter, acetylcholine, allowing choline to be recycled by the presynaptic neurons. If AChE is not effectively hydrolyzed by AChE in this manner, it builds up in the synapse and causes hyperexcitation of the postsynaptic receptors. The metabolites of certain insecticides, such as the phos-phorothionates (e.g., parathion and malathion) inhibit AChE-mediated hydrolysis. Phosphorothionates contain a sulfur atom that is double-bonded to the central phosphorus. However, in a CYP-catalyzed desulfuration reaction, the S atom is... 

Genetic factors account for some ADRs due to either altered pharmacokinetics or by altering tissue responsiveness. Altered metabolism of drugs occurs due to differences in hydrolysis, acetylation, and hepatic oxidation of drugs. Altered pharmacodynamic reactions could be either an exaggerated response or a... 

Drug metabolism occurs primarily in the liver and most commonly involves oxidation, reduction, hydrolysis, and conjugation reactions. Quantitatively, the most important hepatic enzymes are the cytochrome P450 enzymes that have been divided into families and subfamilies (e.g., CYP3A4) based on the similarity of their amino acid sequences. These enzymes are responsible for the metabolism of a large number of drugs. 

Finally, the enzymatic nature of CPIA-cholesterol ester formation will be briefly mentioned. None of the enzyme preparations of three known biosynthetic pathways for cholesterol esters, namely, acyl-CoA cholesterol Q-acyltransferase (ACAT), lecithin cholesterol 0-acyltransferase (LCAT), nor cholesterol esterase, was effective in producing CPIA-cholesterol ester from the Ba isomer or CPIA. In contrast, the 9,000 g supernatant or microsomal fractions from liver or kidney homogenate were found to be capable of producing CPIA-cholesterol ester without the addition of any cofactors. As substrate, only the Ba isomer was effective, and none of the 3 other fenvalerate isomers nor free CPIA was effective. The hepatic enzyme preparation also catalyzed hydrolysis of fenvalerate, and in this case all the 4 isomers were utilized as substrates. These facts imply that CPIA-cholesterol ester is formed from the Ba isomer through a transesterification reaction via intermediary acyl-enzyme complex. 

If readily hydrolyzed. It will be converted to a mercapturlc acid and eliminated as such but It would also be subject to the complex reactions outlined In the preceding chapter. In particular, the product of hydrolysis of an N -malonyl-cystelne conjugate Is the substrate for enterobacterial, hepatic and renal C-S lyases (Figure 4). In certain, albeit rare, circumstances the xenobiotic thiol derived from the action of C-S lyase Is toxic. The now well-documented example of the renal toxicity Induced by hexachlorobutadlene (24) Is a case In point. Such toxicity should be predictable from mammalian metabollsm/toxlclty studies but It would seem to be advisable to have some Information on the fate of N-malonyl cysteine conjugates In general In mammals. In a case where a potentially toxic cysteine conjugate Is found (N-malonylated) In plants It would be necessary to study Its fate In mammals. 

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