Which Cytochrome Enzymes Are Involved In The Metabolism Of Lamotrigine?

Lamotrigine disposition is mediated by UDP-glucuronosyltransferases, mainly by UGT1A4 and UGT2B7, with ABCB1 and SLC22A1 transporters also involved. Polymorphisms in these genes affect protein activity and expression. Lamotrigine is metabolized in the liver primarily by conjugating with glucuronic acid to form the inactive metabolite 2-N-glucuronide. Uridine 5′-diphospho-glucuronosyltransferase 1A4 (UGT1A4) and its neuropsychiatric effects include inhibiting serotonin, dopamine, and noradrenaline uptake.

Lamotrigine exhibits first-order linear pharmacokinetics, with bioavailability approaching 100 and no initial absorption. It employs a more complex mechanism of action, blocking both sodium and N- and L-type calcium channels and modulating H-current. The main metabolite, LTG-N-2-glucuronide (LTG-glu), is mainly glucuronidated, forming an inactive metabolite.

Metabolism of lamotrigine is primarily catalyzed by UGT1A4 and UGT2B7 enzymes, with single-nucleotide polymorphisms (SNPs) in UGT1A4 and UGT2B7 playing a role in inter-individual variability in LTG metabolism. Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase, and uridine diphosphate.

Lamotrigine undergoes extensive metabolism in the liver, primarily by conjugation with glucuronic acid, to various metabolites including 2-N-glucuronide. At higher doses, the enzymes responsible for this metabolism might become saturated. Valproic acid, a CYP enzyme inhibitor, reduces lamotrigine metabolism, increasing serum half-life to 60 hours or more.

Lamotrigine is inactivated by glucuronidation in the liver and is metabolized predominantly by glucuronic acid conjugation. Most commonly used antiepileptics are eliminated through hepatic metabolism, catalyzed by enzymes CYP2C9, CYP2C19, CYP3A4, and uridine.

What drugs are metabolized by CYP 3a4 liver enzymes?

The CYP3A4 protein, located in the endoplasmic reticulum, is responsible for half of the metabolism of approximately 60 prescribed drugs, including acetaminophen, codeine, cyclosporin, diazepam, erythromycin, and chloroquine. It also metabolizes steroids and carcinogens. Most drugs undergo deactivation by CYP3A4, either directly or through facilitated excretion from the body. CYP3A4 also possesses epoxygenase activity, metabolizing arachidonic acid to epoxyeicosatrienoic acids (EETs), which have various activities, including promoting certain types of cancers. CYP3A4 also promotes the growth of various types of human cancer cell lines in culture by producing (±)-14, 15-epoxyeicosatrienoic acids, which stimulate cell growth. CYP3A4 also has fatty acid monooxgenase activity for metabolizing arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE), which has a wide range of activities, including growth stimulation in breast and other types of cancers.

The CYP3A4 gene exhibits a more complicated upstream regulatory region compared to its paralogs, making it more sensitive to endogenous and exogenous PXR and CAR ligands. Chimpanzee and human CYP3A4 are highly conserved in metabolism of many ligands, but four amino acids positively selected in humans led to a 5-fold benzylation of 7-BFC in the presence of the hepatotoxic secondary bile acid lithocholic acid, contributing to an increased human defense against cholestasis.

What is the pharmacokinetics absorption of lamotrigine?

Abstract. The pharmacokinetics of lamotrigine have been studied in single and multiple dose studies in animals, normal volunteers, and patients with epilepsy. Lamotrigine exhibits first-order linear pharmacokinetics. Lamotrigine is well absorbed with bioavailability approaching 100%. The absorption is unaffected by food and there is no first-pass metabolism. The volume of distribution is between 1. 25 and 1. 47 L/kg and protein binding is about 55%. The half-life of lamotrigine is between 24. 1 and 35 hours in drug naive adults but may be altered by enzyme inducing and inhibiting drugs. Clinical trials demonstrated no evidence of autoinduction or saturable metabolism. Younger children (0. 17 to 5 years) eliminate lamotrigine faster than older children (5 to 10 years). Children may be more prone to enzyme induction than adults. (J Child Neurol 1997;12(Suppl 1):S10-S15).

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Dickins M., Sawyer DA, Morley TJ, Parsons DN: Lamotrigine: Chemistry and biotransformation, in Levy RH, Mattson RH, Meldrum BS (eds): Antiepileptic Drugs, 4th ed. New York, Raven Press, 1995, pp 871-875.

How is lamotrigine absorbed by the body?

Lamotrigine is rapidly and entirely absorbed with minimal first-pass metabolism effects, with a bioavailability estimated at 98%. Cmax is reached in the range of 1. 4 to 4. 8 hours post-dose, but this depends on the dose administered, concomitant medications, and epileptic status. The rate and extent of lamictal absorption is considered equivalent between the compressed tablet form taken with water to that of the chewable dispersible tablets, taken with or without water. 14, 15.

The mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranges from 0. 9 to 1. 3 L/kg and is independent of dose administered. Lamotrigine accumulated in the kidney of the male rat, and likely behaves in a similar fashion in humans. Lamotrigine also binds to tissues containing melanin, such as the eyes and pigmented skin. 14, 15.

The plasma protein binding of lamotrigine is estimated at 55%. 11, 14 This drug is not expected to undergo clinically significant interactions with other drugs via competition for protein binding sites due its lower protein binding. 14, 15.

Is lamotrigine metabolized in the liver?

Lamotrigine is metabolized in the liver by glucuronidation, being mainly metabolized by UGT enzymes in the body and excreted by the kidneys, with CYP enzymes not participating in its metabolism.

PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal.

CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal.

Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal.

What drugs induce lamotrigine metabolism?

Consideration for other drugs’ effects on glucuronidation merit consideration, as glucuronic acid conjugation primarily metabolizes lamotrigine.

Drugs that induce lamotrigine glucuronidation include carbamazepine, phenytoin, phenobarbital, rifampin, lopinavir/ritonavir, atazanavir/ritonavir, and primidone.

Valproic acid inhibits lamotrigine glucouronidation.

Concurrent use with central nervous system (CNS) depressants may increase the potency of CNS depression.

What antiepileptic drugs are CYP3A4?

Epilepsy is a prevalent neurological disease with an incidence rate of 44 new cases per 100, 000 person-years. Most patients with epilepsy are treated with antiepileptic agents, which can lead to an increased risk of fractures. This risk is more common with older antiepileptic agents, such as carbamazepine, phenobarbital, phenytoin, primidone, and valproic acid. The increased fracture risk can have serious consequences, such as a 20% mortality rate during the first year after a hip fracture.

One biological mechanism that has been postulated to explain the elevated fracture risk during exposure to older antiepileptics is the induction of the CYP3A4 enzyme, which might result in increased metabolism of the active form of vitamin D to inactive forms. Antiepileptic agents that can induce CYP3A4 include carbamazepine, phenobarbital, phenytoin, and primidone, and at very high concentrations, oxcarbazepine and topiramate. Valproic acid, which does not induce CYP3A4, has also been associated with an increased fracture risk and reduced bone mineral density.

No prior studies have evaluated whether the risk of fracture is higher during long-term exposure to CYP3A4 inducing antiepileptics compared to CYP3A4 non-inducing antiepileptics. This study conducted an observational cohort study using data from The Health Improvement Network (THIN) from 1995 to 2007, which contains electronic medical records from over 380 UK general medical practices and covers more than 1500 general practitioners.

How is lamotrigine metabolised?

LTG, a hormone, has first-order linear pharmacokinetics and is rapidly absorbed into the systemic circulation after oral administration. Its main metabolite, LTG-N-2-glucuronide (LTG-glu), is excreted in urine. The pharmacokinetics of LTG are influenced by factors such as patient age, weight, co-medications, gender, liver and renal function, and specific physiological states like pregnancy. Therapeutic drug monitoring (TDM) may facilitate LTG use.

The reference range for serum LTG concentration in patients treated with therapeutic doses is 2. 5-15 mg l−1 and can be increased or shortened by enzyme-inducing AEDs. However, in patients taking valproic acid, the half-life of LTG is substantially prolonged. LTG has been extensively evaluated in pregnancy and women taking oral contraceptives due to reported decreases in serum LTG concentrations. Polymorphisms in the UGT1A4 and ABCB1 genes have been described that affect protein expression and activity, potentially affecting the clearance of LTG and its concentration in blood plasma and the central nervous system.

Several studies have found significant associations between UGT2B7 –161C T and LTG concentration: dose ratio, with UGT1A4 142G T causing a decrease in LTG concentration in patients carrying this polymorphism. However, no previous study showed a significant association with LTG pharmacokinetics, but UGT2B7 –161C T significantly influenced LTG oral clearance.

The majority of published pharmacogenetic studies with LTG focus on variation in concentration to dose ratio and its association with single gene variability, without considering other factors such as dosing regimen, blood sampling times, and patient-specific covariates. Only one study in a Thai population investigated the influence of specific genetic variants of UGT1A4 and UGT2B7, along with some non-genetic factors, on LTG pharmacokinetics using the population pharmacokinetic approach.

What drugs are CYP2D6?

The enzyme CYP2D6 (Table 66. 4) mediates the metabolism of substrate psychotropic drugs, such as amitriptyline, desipramine, nortriptyline, and cocaine, as well as cardiac drugs, such as debrisoquine, metoprolol, encainide, flecainide, and propafenone (Box 66. 7).

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Is lamotrigine metabolized by CYP3A4?

The drug-drug interaction between lamotrigine and quetiapine is not yet fully understood. Lamotrigine is known to induce its own metabolism through uridine glucuronosyl transferase (UGT) enzymes, which contribute to quetiapine metabolism. A recent study in rats showed that inhibition of UGT led to an elevation of quetiapine exposure, suggesting that UGT enzymes contribute to quetiapine metabolism. However, lamotrigine did not significantly affect the N-desalkylquetiapine-to-quetiapine metabolic ratio, which mainly reflects CYP3A4 metabolism.

The study did not find a correlation between quetiapine C/D ratio and lamotrigine serum concentration, suggesting that the interaction mechanism is related to changes in quetiapine absorption in the intestine. The interaction effect was restricted to the quetiapine IR formulation and not to quetiapine XR.

Quetiapine displayed considerable interindividual variability in C/D ratio, with 120-fold variation for IR tablets and 190-fold variation for XR tablets. Previous studies have also reported great variation in both intra- and interindividual serum concentrations of quetiapine. Due to a short half-life of 7 hours and extreme variability in serum concentration peaks and throughs, it is difficult to eliminate variability due to different sampling times. For IR tablets, through concentration was calculated for 12 hours post-dose to reduce sampling time variability.

Which enzyme metabolizes lamotrigine?

The elimination of lamotrigine is mainly by hepatic metabolism to the glucuronide conjugate (Article:1773780). UDP glucuronosyltransferase 1 family, polypeptide A4 (UGT1A4) was found to be involved in lamotrigine metabolism (Articles:11927765, 11593076).

What drugs are CYP3A4 inhibitors?

• Key Messages. CYP3A4 is responsible for the metabolism of more than 50% of medicines.
• CYP3A4 activity is absent in new-borns but reaches adult levels at around one year of age.
• The liver and small intestine have the highest CYP3A4 activity.
• Some important CYP3A4 interactions are due to intestinal rather than hepatic enzyme inhibition (eg, grapefruit).
• There is considerable variability in CYP3A4 activity in the population.
• Women have higher CYP3A4 activity than men.
• Potent inhibitors of CYP3A4 include clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit.
• Inducers of CYP3A4 include phenobarbital, phenytoin, rifampicin, St. John’s Wort and glucocorticoids.

Cytochrome P450 enzymes are essential for the metabolism of many medicines and endogenous compounds. The CYP3A family is the most abundant subfamily of the CYP isoforms in the liver. There are at least four isoforms: 3A4, 3A5, 3A7 and 3A43 of which 3A4 is the most important 1.

CYP3A4 contributes to bile acid detoxification, the termination of action of steroid hormones, and elimination of phytochemicals in food and the majority of medicines 2, 3.