Is phenytoin metabolized in the liver?
Phenytoin is highly (>90%) protein-bound and is extensively metabolized by the liver. Less than 5% of the drug is excreted unchanged in the liver. Phenytoin exhibits nonlinear (e.g., Michaelis-Menton) pharmacokinetics, indicating that the metabolismsaturates at doses given clinically.
How is phenytoin metabolized?
Phenytoin is metabolized by cytochrome P450 (P450) enzymes primarily to 5-(p-hydroxyphenyl-),5-phenylhydantoin (HPPH), which may be further metabolized to a catechol that spontaneously oxidizes to semiquinone and quinone species that covalently modify proteins.
How does phenytoin affect the liver?
Phenytoin is an anticonvulsant that in rare cases can cause acute idiosyncratic drug-induced liver disease that can be severe or even fatal. The liver injury caused by phenytoin appears to be due to a hypersensitivity reaction and resembles cases of immunoallergic hepatotoxicity.
What is the pharmacokinetics of phenytoin?
Hepatic microsomal enzymes primarily metabolize phenytoin. Much of the drug is excreted in the bile as an inactive metabolite, which is then reabsorbed from the intestinal tract and ultimately excreted in the urine. Less than 5% of phenytoin is excreted unchanged in the urine.
How is valproic acid metabolized?
VPA is a fatty acid and can be metabolized via endogenous pathways in the mitochondria. It has been observed that some of the mitochondrial metabolites of VPA generated by this pathway are hepatotoxic. VPA crosses the membrane of liver mitochondria via the facilitation of carnitine.
What does Dilantin do to the liver?
Anti-seizure medications are generally a problem, as several anti-epileptic medications can cause liver damage. Dilantin (phenytoin) can cause liver damage shortly after you start taking it, which is why you will need regular lab tests to monitor your liver functioning.
Does phenytoin have active metabolites?
Metabolizing enzymes. Phenytoin is primarily metabolized to the inactive hydroxyphenytoin, 5-(4′-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) (Fig. 1) [2]. Up to 90% of phenytoin is metabolized to p-HPPH and then glucuronidated and excreted into the urine [3].
How does Dilantin affect your liver?
6) Anti-seizure medications Dilantin (phenytoin) can cause liver damage shortly after you start taking it, which is why you will need regular lab tests to monitor your liver functioning. Carbamazepine and lamotrigine can also cause liver injury, which may show up after you’ve been taking either for weeks to months.
Is phenytoin safe in liver disease?
Drugs such as valproic acid, phenytoin, and felbamate, have a well-recognized association with liver toxicity. Other antiepileptic drugs, including phenobarbital, benzodiazepines, ethosuximide, and the newer generations of antiepileptic drugs, have only rarely been linked to hepatotoxicity.
What is first order elimination?
Definition. First-order elimination kinetics depends on the concentration of only one reactant (drug) and a constant fraction of the drug in the body is eliminated per unit time. The rate of elimination is proportional to the amount of drug in the body. The majority of drugs are eliminated in this way.
Does phenytoin have saturable metabolism?
The metabolism of phenytoin to the major metabolite, 5-(p-hydroxyphenyl)-5-(phenylhydantoin, is saturable, giving rise to a non linear dose-serum concentration relationship.
Is Depakote metabolized by the liver?
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate.
How is phenytoin metabolized to its inactive form?
Phenytoin is primarily metabolized to its inactive form by the enzyme CYP2C9. Variations within the CYP2C9 gene that result in decreased enzymatic activity have been associated with increased phenytoin concentrations, as well as reports of drug toxicities due to these increased concentrations.
How long does it take for phenytoin to reach steady state?
Phenytoin elimination kinetics show mixed-order behaviour at therapeutic concentrations. A small increase in dose may lead to a large increase in drug concentration as elimination becomes saturated. The time to reach steady state is often longer than 2 weeks.
How does phenytoin inhibit the absorption of folate?
Folate is present in food in a polyglutamate form, which is then converted into monoglutamates by intestinal conjugase to be absorbed by the jejunum. Phenytoin acts by inhibiting this enzyme, thereby causing folate deficiency, and thus megaloblastic anemia.
What happens to drug metabolising enzymes after oral administration?
After oral administration, the drug-metabolising enzymes in the liver are exposed to relatively high drug concentrations in the portal blood. For drugs with high hepatic extraction ratios, e.g. alprenolol, an increased dose can result in saturation of the metabolising enzymes and an increase in bioavailability (F).