Hepatic enzyme systems

Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate glucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzyme systems and displaces some drugs from plasma albumin. 

The present study was undertaken to determine the influence of several levels of dietary casein upon the activities of trout hepatic enzyme systems which may be involved in the in vitro activation and detoxification of AFB. In addition, the effect of Technical Paper No. 4883, Oregon Agricultural Experiment Station. 

Metabolism - Cyclosporine is metabolized by the cytochrome P-450 3A4 hepatic enzyme system. 

Darunavir both inhibits and is metabolized by the CYP3A enzyme system, conferring many possible drug-drug interactions (Table 49-3). In addition, the co-administered ritonavir is a potent inhibitor of CYP3A and CYP2D6, and an inducer of other hepatic enzyme systems. 

The metabolism of lorazepam (e.g., Ativan), oxazepam (e.g., Serax), and temazepam (e.g., Restoril) are not likely to be affected, and one of these agents may be preferred when a benzodiazepine is indicated in a patient being treated with cimetidine. The experience with ranitidine (e.g., Zantac), famotidine (Pepcid), and nizatidine (Axid) suggests that these agents are not likely to inhibit hepatic enzyme systems, and these other histamine H2-receptor antagonists are less likely than cimetidine to interact with other drugs that are metabolized via these pathways. 

Fluoroquinolones. Ciprofloxacin and enoxacin (Pene-trex) may markedly increase serum concentrations of medications such as theophylline by inhibiting their hepatic metabolism. Certain other fluoroquinolones, such as levofloxacin (Levaquin), are not likely to inhibit hepatic enzyme systems and interact with these medications. 

E Itraconazole. Imatinib is primarily metabolized by the CYP3A4 hepatic enzyme system. Drugs that may inhibit this enzyme (such as ketoconazole, itraconazole, erythromycin, clarithromycin, etc.) may impair clearance of imatinib and result in increased toxicity. Imatinib itself is also a fairly potent inhibitor of the CYP3A4 enzyme and may result in toxicity due to other drugs that are substrates for this enzyme (such as simvastatin, warfarin, benzodiazepines, etc.). The other medications iisted are uniikeiy to affect the function of 0 P3A4 or interact adversely with imatinib. 

Metals can inhibit the hepatic enzyme system and affect the metabolism of VOCs. Rats pretreated with zinc chloride decreased CYP450 and protected CCI4 liver damage. The effects of exposure to metals on the metabolism of solvents are more pronounced in acute situations than chronic at high doses. 

Proteins are not cleared by hepatic enzyme systems. Flowever, fiver size and function, spleen function, and macrophage function would be expected to account for variability in observed clearance of large therapeutic proteins. For instance, Sewell et al. (68) demonstrated that Kupffer cell function is decreased in aged rats, which is a function of age as much as it is of liver function. Standard measures of liver function such as alanine transferase may not provide relevant information and are rarely identified as a covariate even with small molecules. Flowever, patients with advanced liver disease such as cirrhosis may have reduced clearance due to poor liver function and reduced liver blood flow. 

Aluminum-containing antacids may decrease the absorption of quinine. Quinine may depress the hepatic enzyme system that synthesizes the vitamin-K-dependent clotting factors and thus may enhance the action of warfarin and other oral anticoagulants. Cimetidine may reduce quinine s oral clearance and increase its elimination half-life. Digoxin serum concentrations may be inaeased by concurrent quinine. 

These are active orally and. although most are metabolized by oxidation in Ihe liver, they do nm induce hepatic enzyme systems. Hiey are cciiiral depressants but. in contrast to other hypnotics and anxiolytics, their maximum effect when given orally docs not noimally cause fatal, or even... 

The long-term use of alcohol can cause induction of hepatic enzyme systems possibly resulting in increased metabolism and reduced plasma levels of carbamazepine. The risk of seizures may also increase on tapering or stopping alcohol because of an increase in metabolism and elimination caused by the relative lack of a competing substrate. ... 

Caffeine is also a xanthine and it is principally used as a central nervous system stimulant, increasing wakefulness, and mental and physical activity. It is most commonly taken in the form of tea, coffee, cola drinks ( Coke") and cocoa. Table 33.2 , (p.l 159) lists the usual caffeine content of these drinks. Caffeine is also included in hundreds of non-prescription analgesic preparations with aspirin, codeine and/or paracetamol, but whether it enhances the analgesic effect is debatable. Caffeine is also used to assess the activity of hepatic enzyme systems (particularly the cytochrome P450 isoenzyme CYP1A2) and can usefully demonstrate altered liver function, notably from drugs, as well as disease states. 

Studies aimed at the identification of the hepatic enzyme systems which are induced or inhibited by estrogens, thyroxine and clofibrate type hypolipidemic agents may also afford guidelines for the development of antiatherosclerotic agents. 

Lidocaine is primarily metabohzed by the cytochrome P450 hepatic enzyme system into active but less potent metabohtes, mainly monoethyl-glycinexy-lidide (MEGX). Lidocaine has a half-life of 1.5-2.5 hours and is excreted mainly via the renal system. 

The authors conclude that the cause for the CNS toxicity may have been multifactorial including small size of the infant, high concentration and volume of the local anesthetic agent, the choice of bupivacaine, the immaturity of the hepatic enzyme systems and lower levels of alpha-l-acid glycoprotein in the newborn. 

The elimination of caffeine is impaired in neonates because of their immature metabolizing hepatic enzyme systems. For example, plasma half-lives of 65-103 h in neonates have been reported compared to 3-6 h in adults and the elderly. 

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