Comparison of Plasma and Saliva Concentrations of Lamotrigine in Healthy Volunteers

Abstract

The relationship between lamotrigine (CAS 84057-84-1) concentrations in saliva and plasma in healthy volunteers were examined, as well as the possibility of using saliva to monitor levels for effective therapy. The study was performed with 14 healthy volunteers, mean age 23 +/- 2 (SD) years. After single oral doses of 200 mg, plasma and stimulated saliva samples were collected simultaneously at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 and 96 h. The pH values of saliva samples were recorded. Lamotrigine concentrations were determined by a validated HPLC method. Fraction of drug bound to plasma proteins was calculated mathematically by the modified Henderson-Hasselbalch equation. Linear regression was used to evaluate the correlations. The remnant of orally administered drug contaminated the saliva samples and gave spuriously high values for up to 2 h, which were omitted. There was significant correlation (r2 = 0.677, p < 0.0001) between plasma and saliva concentrations from 2-96 h after administration. The mean ratio of saliva to plasma concentration was 0.426 +/- 0.153 (mean +/- SD). Protein binding, calculated from the concentrations in saliva was 57.5 +/-15.1% (mean +/- SD). Noncompartmental analysis was conducted with the program Kinetica. Plasma t1/2 and MRT were not significantly different from those found from saliva. The mean values of lamotrigine peak saliva concentrations (C(max)), areas under the curve of concentration versus time from zero to infinity (AUC(0-->infinity)), and areas under the curves of the product of time and concentration versus time from zero to infinity (AUMC(0-->infinity) were proportionally lower than in plasma. The results support the use of saliva concentration as a convenient, painless and noninvasive alternative to plasma for monitoring lamotrigine therapy.

Therapeutic Drug Monitoring of Antiepileptic Drugs by Use of Saliva

“…64 In specimens collected $2 hours after ingestion, there was a close correlation in each individual between the concentrations in stimulated and unstimulated saliva, which were similar. 121 Furthermore, the mean saliva/serum lamotrigine concentration ratio was 0.425 6 0.153, and the calculated protein binding from the concentration in saliva was 57.5 6 15.1% (mean 6 SD); thus, saliva concentrations reflect the free concentrations in serum. 64 A study in 14 healthy volunteers comparing saliva and serum lamotrigine concentrations over 96 hours after ingestion of a single oral dose of lamotrigine reported significant correlation between saliva and serum (r 2 = 0.677).…”

Tolerability, pharmacokinetics, and bioequivalence of the tablet and syrup formulations of lacosamide in plasma, saliva, and urine: Saliva as a surrogate of pharmacokinetics in the central compartment

“…Previous studies have shown that for some AEDs the saliva‐to‐total‐plasma drug concentration ratio is an indirect measure of drug plasma protein binding (Fuse et al., 2005; Incecayir et al., 2007). For AEDs, only unbound drug can cross biologic barriers that separate tissue compartments (Drobitch & Svensson, 1992); therefore, a low ratio of saliva to total drug is indicative of high plasma protein binding, whereas a ratio closer to 1 is indicative of minimal plasma protein binding.…”

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…Lamotrigine distributes into saliva, with salivary lamotrigine concentrations being on average approximately 0.4–0.5 that of serum concentrations in patients receiving chronic lamotrigine therapy. Salivary lamotrigine concentrations correlate well with those in serum, which makes saliva an alternative sample to perform TDM [83,84]. The parent drug is extensively metabolized, mainly by glucuronidation to an inactive metabolite [85].…”