Tears as the Best Practical Indicator of the Unbound Fraction of an Anticonvulsant Drug

Abstract

Phenobarbital and carbamazepine concentrations were determined by the EMIT technique in tears, saliva, cerebrospinal fluid (CSF), and plasma of patients with epilepsy. Closer correlation was shown between tear/plasma and tear/CSF ratios than between saliva/plasma and saliva/CSF ratios for the two agents. The phenobarbital CSF/serum ratio was in good agreement with data in the literature, and the higher ratio found for carbamazepine may be caused by an EMIT assay cross-reaction for the free fraction of carbamazepine-10,11-epoxide. In our hands, tears seem to represent the best practical indicator of the unbound fraction of an anticonvulsant drug, and the noninvasiveness of the method makes it specifically useful in pediatric neurology.

Lachrymal Determinations: Methods and Updates on Biopharmaceutical and Clinical Applications

“…A significant portion of the agent passed through loose junctions of the acinous epithelium presents in lachrymal glands. Carbamazepine and phenobarbital levels in tears are twice lower than in plasma [3,97]. Stoehr et al [98] have observed a stronger correlation with plasma versus tears (r = 0.94) than with plasma versus saliva (r = 0.84).…”

“…Standardisation of experimental procedure may hinder tearing reflex or evaporation and ensures stability of the compounds determined in lachrymal fluid [3]. Different procedures have been proposed.…”

“…(a) chemical stimuli: gas like bromacetone [6,34], fumes (or vapor) of liquid agents like ethanol, formalin or ammonium [3,35,36] or cigarette fumes [37]; (b) physical stimuli: intensive light [38], mechanical stimuli by means of gentle aggression on the cornea (puff of air, fine brush, little sponge placed against the lower fornix) [15,37,39,40,41] and (c) physiological stimuli: the tearing reflex can be induced by a sneezing or yawning stimulation, which presents the great advantage of not altering ocular structures [14,42,43].…”

“…It plays a tensioactive role, ensures moisture of the cornea, allows blinking and enhances tear elimination. Its main physical and chemical composition is the following [1,2]: density 1.004-1.005; pH 6.5-7.5; osmolality 318 mosm/l; temperature 30-35°C; viscosity 1.260 mPa W s; composition: H 2 O 98%, CO 2 27.5 mm Hg, Na + 134-170 mmol/l, K + 20-40 mmol/l, HCO 3 -26 mmol/l, phosphorus 8-10 mmol/l, protein 6-10 g/l; volume and flow characteristics in humans: lachrymal volume 6-7 Ìl/min, basic flow 1.2 Ìl/min (0.5-2.2 Ìl/min), maximal capacity: 30 Ìl without blinking.…”

Valproic acid fails to displace phenobarbitone and carbamazepine from plasma protein binding sites in epileptic patients.

“…Plasma and mixed saliva samples were collected for each patient immediately before and 15 and 45 min after intravenous administration of single dose (1200 mg) of sodium valproate (Sigma-Tau, Italy). The plasma and saliva levels of (Schottelius, 1978;Monaco et al, 1979;Paxton & Donald, 1980). Valproic acid in plasma was determined in duplicate by gas-liquid chromatography (Kupferberg, 1978).…”