Aims Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood±brain-barrier and the consequent occupation of brain histamine H 1 -receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second-generation antihistamine, with cognitive performance tests. In the present study, H 1 -receptor occupation by ebastine was examined in the human brain using PET. Methods Ebastine 10 mg and (+)-chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11 C]-doxepin, a potent H 1 -receptor antagonist, were conducted near t max of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP=Bmax/ K d ) for available brain H 1 -receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H 1 -receptor occupancy of drugs was calculated in several H 1 -receptor rich regions. Results Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)-chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H 1 -receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were signi®cantly higher than after (+)-chlorpheniramine (2 mg). H 1 -receptor occupancies in cortex were approximately 10% by ebastine and i50% by either dose of (+)-chlorpheniramine (95% con®dence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)-chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine. Conclusions Ebastine (10 mg orally) causes brain histamine H 1 -receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H 1 -receptors even at a low but sedative dose of 2 mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.

Aims It has been widely recognized that classical antihistamines induce sedation as an adverse effect, while second-generation antihistamines have few if any sedative effects. In order to evaluate the sedative properties of ebastine, a second-generation antihistamine, its effect on cognitive performance in healthy subjects was compared with placebo and (+)-chlorpheniramine. Methods Twelve healthy male subjects were instructed to perform six types of attention-demanding cognitive tasks, and objective measurements of reaction times and accuracy was made before and after drug administration. Their sleepiness levels were also monitored. Test drugs were ebastine 10 mg, placebo and two doses of (+)-chlorpheniramine 2 mg and 6 mg, as positive controls. Plasma drug concentrations at the end of the study were analysed. Results After treatments with (+)-chlorpheniramine, the reaction times of the tasks were signi®cantly prolonged (e.g. ratios of after/before dosing: placebo (0.998t0.113) vs (+)-chlorpheniramine 2 mg (1.103t0.083; P<0.05) or (+)-chlorpheniramine 6 mg (1.170t0.139; P<0.001) in a 7 ms visual discrimination time task) and the accuracy was signi®cantly decreased (e.g. ratios: placebo (1.038t0.158) vs (+)-chlorpheniramine 2 mg (0.792t0.202; P<0.01) or (+)-chlorpheniramine 6 mg (0.837t0.222; P<0.05) in a 7 ms task). On the other hand, performance was not affected by ebastine or placebo treatment (e.g. ebastine 10 mg (reaction time ratio; 1.014t0.067 and accuracy ratio; 0.990t0.146) in a 7 ms task). Subjective sleepiness was also not affected by ebastine but (+)-chlorpheniramine signi®cantly increased sedation. With respect to the relationship between plasma drug concentrations and task performance, the latter deteriorated with an increase in plasma (+)-chlorpheniramine concentration (e.g. r=0.439 (P=0.007) in a 5 ms and r = 0.352 (P=0.039) in a 7 ms task), but it did not correlate with the plasma concentration of carebastine, an active metabolite of ebastine. Conclusions Ebastine 10 mg did not cause any cognitive impairment or subjective sleepiness. On the other hand, (+)-chlorpheniramine impaired cognitive function and induced sleepiness even at 2 mg, the recommended dose in over-the-counter medication. In addition, impaired CNS performance was signi®cantly correlated with plasma (+)-chlorpheniramine concentration.

This article is available online at http://dmd.aspetjournals.org In the pharmaceutical industry, dogs are commonly used as a nonrodent species for toxicological and pharmacological studies of drug candidates. In addition, dog pharmacokinetic data along with in vitro metabolic data can be very useful for the prediction of human in vivo pharmacokinetics and interpretation of toxicity and efficacy results in both species. However, remarkable interindividual difference of drug concentration in plasma is frequently observed in dogs after drug administration (Paulson et al., 1999;Azuma et al., 2002). This variability of pharmacokinetics often affects the results of toxicological and pharmacological studies. Therefore, it is important for efficient and reliable preclinical studies to clarify the mechanism of pharmacokinetic variability and to remove the factors affecting it.Cytochrome P450 (P450 1 ) plays a decisive role in the oxidative metabolism of xenobiotics and endogenous substances (Rendic and Di Carlo, 1997). In humans, many genetic polymorphisms of P450 have been reported, and some of them are considered important factors for interindividual variability of drug metabolism and pharmacokinetics (http://www.imm.ki.se/CYPalleles/). On the other hand, in dogs several P450s have been cloned and sequenced, including CYP1A1/2 (Uchida et al., 1990), CYP2B11 (Graves et al., 1990), CYP2C21/41 (Uchida et al., 1990;Blaisdell et al., 1998), CYP2D15 (Sakamoto et al., 1995, CYP2E1 (Lankford et al., 2000), and CYP3A12/26 (Ciaccio et al., 1991;Fraser et al., 1997). However, the contribution of these P450s to the interindividual variability of pharmacokinetics in dogs is unknown.5-(3-Methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine (AC-3933) is a novel cognitive enhancer with central benzodiazepine receptor partial inverse agonistic activity. The mechanism of AC-3933's memory-improving action is based on enhancement of the cholinergic function through the allosteric reduction of ␥-aminobutyric acid activity. In dogs, AC-3933 is metabolized to a major hydroxylated metabolite (SX-5745) and a minor demethylated metabolite (SX-5773), and subsequently, SX-5745 is reductively metabolized to SX-6088 (Fig. 1). This report describes a polymorphism in AC-3933 pharmacokinetics in dogs, and C]-1,6-naphthyridine; SX-5745, 3-(5-hydroxymethyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridine; SX-5773, 5-(3-hydroxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine; SX-6088, 5-(3-methoxyphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylic acid; EM, extensive metabolizer; PM, poor metabolizer; C 3h , concentration at 3 h after administration; HPLC, high-performance liquid chromatography; EROD, ethoxyresorufin O-deethylase; POD, phenacetin O-deethylase; ECOD, ethoxycoumarin O-deethylase; APND, aminopyrine N-demethylase; AUC 0-24 , area under concentration-time curve from zero to 24 h.

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