Sodium valproate acutely inhibits lamotrigine metabolism.

Abstract

Concomitant administration of sodium valproate (VPA) reduced lamotrigine (LTG) total clearance by approximately 21% and increased elimination half-life and AUC. Reduced elimination occurred acutely within the first hour. Renal elimination of LTG was not impaired. The most probable explanation for this effect is hepatic competition between VPA and LTG for glucuronidation. Volume of distribution and parameters related to absorption, Cmax and tmax were unchanged.

In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)

“…CYP2C19, CYP2D6 and CYP3A4 seem to be the major enzymes mediating the metabolism of amitriptyline, but CYP2C9 is also involved [39] and a small fraction of the dose is eliminated via direct glucuronidation [40]. Consequently, the inhibitory effects of valproic acid on CYP2C9 and UDP-glucuronyltransferases [37,41] probably explain the valproic acid-phenobarbitone [4±7] and valproic acid±amitriptyline interactions [10]. In conclusion, valproic acid inhibits CYP2C9 activity in vitro in human liver microsomes, with an apparent K i value of 600 mM.…”

Pharmacokinetics and Interaction Profile of Topiramate: Review and Comparison with Other Newer Antiepileptic Drugs

“…The plasma half-life of VGB is 5-8 h, and renal clearance accounts for approximately 70% of total clearance (22,23). VGB is not bound to plasma proteins (34).…”

Inhibition of phenobarbitone N‐glucosidation by valproate.

“…In animals, valproate is known to inhibit the glucuronidation of certain substrates, including p-hydroxyphenobarbitone [16,22] and, in humans, of lamotrigine [23]. This inhibition appears likely to be due to depletion of hepatic UDPglucuronic acid by valproate [24].…”