Liver tissue phenytoin

Another important group of hydrolytic enzymes are the epoxide hydrolases, also known as epoxide hydrase or epoxide hydratase, most commonly found in liver tissue. Epoxide hydrolases catalyze the hydration of arene oxides and aliphatic epoxides to their corresponding /raKt-dihydrodiols or diols, respectively, by activating a water molecule to attack one of the carbons of the arene oxide or epoxide [41]. Although one of the major metabolites of carbamazepine is the stable epoxide, this metabolite also undergoes hydrolysis to form the trans-dial metabolite (Fig. 3). Likewise, the anticonvulsants phenytoin and mephenytoin form arene oxides, which then form trans-dihy-drodiol that undergo further oxidation to form the catechols by the enzyme dihydrodiol dehydrogenase (Fig. 11) [42,43]. 

An in vitro investigation found that fluoxetine and fluvoxamine inhibited the metabolism of phenytoin by the cytochrome P450 isoenzyme CYP2C9 in human liver tissue. This would presumably lead to a rise in serum phenytoin levels. In this study, sertraline was a weaker inhibitor of CYP2C9, and was considered less likely to interact with phenytoin.A similar study also suggested that the risk of interaction was greatest for fluoxetine, and less likely with sertraline and paroxetine. Sertraline plasma levels may be reduced because of enzyme induction by phenytoin which would increase its metabolism and clearance from the body. ... 

The clearance of a drug is usually defined as the rate of elimination of a compound in the urine relative to its concentration in the blood. In practice, the clearance value of a drug is usually determined for the kidney, liver, blood or any other tissue, and the total systemic clearance calculated from the sum of the clearance values for the individual tissues. For most drugs clearance is constant over the therapeutic range, so that the rate of drug elimination is directly proportional to the blood concentration. Some drugs, for example phenytoin, exhibit saturable or dose-dependent elimination so that the clearance will not be directly related to the plasma concentration in all cases. 

After an oral dose of the sodium salt, peak plasma phenytoin levels occur from one (H5) to between 4 and 8 hours (D5) later. After either oral or intravenous administration, phenytoin accumulates rapidly in organs such as the liver, kidney, and salivary glands, and maximum levels are reached within 30 minutes even in tissues such as the brain and skeletal muscle, which accumulate phenytoin more slowly. Uptake by fat is delayed (N5). 

Gamma-glutamyl transferase (GGT) is found in the liver, but this test is relatively non-specific. It is released following tissue damage and is raised in cholestasis in parallel with ALP. GGT release is stimulated by alcohol and some drugs (such as phenytoin and carbamazepine), and therefore the GGT level can be used to assess abstinence in alcoholics, like Mrs MW. 

In a 5-year-old child who died following the ingestion of flurazepam and phenobarbitone, the following postmortem tissue concentrations were reported for flurazepam, A -desalkylflurazepam and A -(2-hydroxy-ethyl)flurazepam, respectively blood 3.2, 1.8 and 2.5pg/ml brain 0.8, 0.7 and 0.7 pg/g, kidney 0.9, 0.6 and 1.1 pg/g, liver 2.7, 3.1 and 3.5 pg/g. Phenobarbitone concentrations were consistent with a therapeutic dose and low concentrations of phenytoin were also detected (S. D. Ferrara et al., J.forens. Sci., 1979, 24, 61-69). 

Phenytoin sodium is located in high amounts in the body tissues, especially fat and liver, leading to large gradients... 

Measurement of serum y-GT activity has clinical significance. The enzyme is present in all tissues, but the highest level is in the kidney however, the serum enzyme originates primarily from the hepatobiliary system. Elevated levels of serum y-GT are found in the following disorders intra- and posthepatic biliary obstruction (elevated serum y-GT indicates cholestasis, as do leucine aminopeptidase, 5 -nucleotidase, and alkaline phosphatase) primary or disseminated neoplasms some pancreatic cancers, especially when associated with hepatobiliary obstruction alcohol-induced liver disease (serum y-GT may be exquisitely sensitive to alcohol-induced liver injury) and some prostatic carcinomas (serum from normal males has 50% higher activity than that of females). Increased activity is also found in patients receiving phenobarbital or phenytoin, possibly due to induction of y-GT in liver cells by these drugs. 

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