Urinary excretion of valproate metabolites in children and adolescents

Reith, David; Andrews, Jaymie; Parker, Suzanne L.; Eadie, Mervyn J.

doi:10.1002/bdd.247

Cited by 10 publications

(10 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a study of 18 normal volunteers, Yau et al (28) found that the elimination half‐life of LTG decreased by 25%, and the oral plasma clearance increased by 37% after 14 days of LTG treatment. Coadministration of LTG also results in an increase in VPA clearance by ∼25%(38) and an increased excretion of VPA glucuronide (30). Mechanistically, starting with a lower dose of LTG and increasing at a slow rate would allow time for the autoinduction of UGT metabolism of LTG to the nontoxic N‐glucuronide metabolites.…”

Section: Lamotrigine and Rashsupporting

confidence: 62%

“…VPA plasma clearance is increased in young children compared with that in adults; however, glucuronidation does not appear to be responsible for the increased clearance. Reith et al found that the proportion of dose recovered as VPA glucuronide in children less than 10 years was lower, not greater, than in children greater than 10 years (30). Other investigators found an increase in the formation of oxidative metabolites of VPA in children compared with adults (31), but the data are limited.…”

Section: Effect Of Age On Pharmacokinetics In Childrenmentioning

confidence: 98%

See 1 more Smart Citation

Children Versus Adults: Pharmacokinetic and Adverse‐Effect Differences

Anderson¹

2002

Epilepsia

156

102

View full text Add to dashboard Cite

Summary: Pharmacokinetic differences may play a part in the age-related differences in the incidence of adverse effects. The most common idiosyncratic reaction to lamotrigine (LTG) is rash, affecting 10-20% of patients. Risk factors are young age, concurrent valproate (VPA), high starting dose, and rapid escalation. In children, cytochrome P450 (CYP)-catalyzed metabolism is increased, and uridine diphosphate (UDP)-glucuronosyltransferase (UGT)-catalyzed metabolism is not significantly different from that in adults. A CYP-catalyzed arene oxide intermediate of LTG has been identified. The increase CYP metabolism of LTG in children could result in increased formation of the reactive metabolite and a higher incident of rash. Children often received higher milligram per kilogram doses compared with adults. The higher dose would cause an increased amount of LTG metabolized to the reactive arene oxide intermediate. VPA therapy is associated with a transient elevation in liver-function tests in 15-30% of patients and a rare, fatal hepatotoxicity. Most cases of VPA hepatotoxicity occurred in children younger than 2 years who had preexisting neurologic or other physical defects. Hypotheses regarding the pathogenesis of the hepatotoxicity include preexisting mitochondrial disease or inborn errors of metabolism, VPA inhibition of ␤-oxidation, and toxicity from VPA metabolites VPA, 4-ene-VPA, and 2,4-diene-VPA. Infants and children have higher concentration ratios of 4-ene-VPA to VPA. Polytherapy with enzyme inducers increases the formation of the hepatotoxic metabolites. The role of underlying metabolic disorders associated with hepatodegeneration and intractable seizures without VPA is a major confounder in identifying risk factors and demonstrates the difficulty in separating underlying disease factors in rare idiosyncratic reactions. Key Words: Antiepileptic drugs-Pharmacokinetics-Children-LamotrigineValproate.Many physiologic differences between neonates, infants, children, and adults can affect the absorption, distribution, metabolism, and excretion of antiepileptic drugs (AEDs) ( Table 1). The purpose of this article is to (a) provide a brief review of the pharmacokinetic differences between children and adults, and (b) to theorize how pharmacokinetic differences may play a part in the age-related differences in the incidence of adverse effects. Two idiosyncratic reactions, lamotrigine (LTG) rash and valproate (VPA) hepatotoxicity are discussed. For further information about the effects of age on the pharmacokinetics of AEDs, Battino et al. (1,2) recently published an extensive review of the pharmacokinetics of the AEDs in children. EFFECT OF AGE ON PHARMACOKINETICS IN CHILDREN AbsorptionNeonates and infants undergo significant maturation changes in gastric and intestinal pH, gastrointestinal (GI) emptying time, circulation, enzyme activity, and difference in GI flora (3,4). However, because of a lack of clinical studies, relatively little is known regarding the effects of GI maturation on the rate and extent of absor...

show abstract

Section: Lamotrigine and Rashsupporting

confidence: 62%

Section: Effect Of Age On Pharmacokinetics In Childrenmentioning

confidence: 98%

Children Versus Adults: Pharmacokinetic and Adverse‐Effect Differences

Anderson¹

2002

Epilepsia

156

102

View full text Add to dashboard Cite

show abstract

“…It is commonly thought that cytochrome P450 (CYP) enzymes, mitochondrion-mediated β-oxidation, and glucuronosyltransferases (UGTs) are the 3 main metabolic routes of VPA [17]. Glucuronide metabolites account for 50% of the VPA dose [18,19]; therefore, it plays an important role in metabolism of VPA.…”

Section: Discussionmentioning

confidence: 99%

Association of UGT2B7 and UGT1A4 Polymorphisms with Serum Concentration of Antiepileptic Drugs in Children

Jiao

Shi

2016

Med Sci Monit

View full text Add to dashboard Cite

BackgroundThis study aimed to analyze the relationship of UGT2B7 and UGT1A4 polymorphisms with metabolism of valproic acid (VPA) and lamotrigine (LTG) in epileptic children.Material/MethodsWe administered VPA (102) and LTG (102) to 204 children with epilepsy. Blood samples were collected before the morning dose. Serum concentration of LTG was measured by high-performance liquid chromatography (HPLC). Serum VPA concentration was tested by fluorescence polarization immunoassay. UGT2B7 A268G, C802T, and G211T polymorphisms, as well as UGT1A4 L48V polymorphism, were assayed by direct automated DNA sequencing after PCR. Evaluation of efficacy was conducted using the Engel method.ResultsThe adjusted serum concentration of VPA was 4.26 μg/mL per mg/kg and LTG was 1.56 μg/mL per mg/kg. Multiple linear regression analysis revealed that VPA or LTG adjusted concentration showed a good linear relation with sex and age. UGT2B7 A268G and C802T polymorphisms were demonstrated to affect the serum concentration of VPA (F=3.147, P=0.047; F=22.754, P=0.000). UGT1A4 L48V polymorphism was not related with the serum concentration of LTG (F=5.328, P=0.006). In the efficacy analysis, we found that C802T polymorphism exerted strong effects on efficacy of VPA (χ2=9.265, P=0.010). L48V polymorphism also showed effects on efficacy of LTG (χ2=17.397, P=0.001).ConclusionsUGT2B7, UGT1A4 polymorphisms play crucial roles in metabolism of VPA and LTG.

show abstract

“…Although the exact mechanisms underlying this individual variability remain elusive, concomitant medications and genetic polymorphisms represent two major causes of this phenomenon (Anderson, 1998;Chung et al, 2008;Nakajima et al, 2004;Patsalos and Perucca, 2003;Perucca, 2006). VPA is metabolized via three routes, catalyzed by various cytochrome P450 (CYP) enzymes, mitochondrionmediated ␤-oxidation, and glucuronidation; this is catalyzed by uridine diphosphate glucuronosyltransferases (UGTs) (Reith et al, 2000;Zaccara et al, 1988). Many studies have reported that genetic polymorphisms of phase I metabolic enzymes, including CYP2C9, CYP2C19, CYP2A6, and CYP2B6, influenced the pharmacokinetics of VPA.…”

Section: Introductionmentioning

confidence: 99%