Peripheral and central H1 histamine receptor occupancy by levocetirizine, a non‐sedating antihistamine; a time course study in the guinea pig

• Published in: British journal of pharmacology 2007-08, Vol.151 (7), p.1129-1136
• Main Authors: Gupta, A, Gillard, M, Christophe, B, Chatelain, P, Massingham, R, Hammarlund‐Udenaes, M
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-Allergic Agents - administration & dosage; Anti-Allergic Agents - pharmacokinetics; antihistamines; Biological and medical sciences; Blood-Brain Barrier - metabolism; Brain - metabolism; brain pharmacokinetics; Cerebellum - metabolism; Cetirizine - administration & dosage; Cetirizine - blood; Cetirizine - pharmacokinetics; Chlorpheniramine - administration & dosage; Chlorpheniramine - blood; Chlorpheniramine - pharmacokinetics; Chromatography, Liquid; Dose-Response Relationship, Drug; FARMACI; Guinea Pigs; H1 receptor occupancy; Half-Life; Histamine H1 Antagonists, Non-Sedating - administration & dosage; Histamine H1 Antagonists, Non-Sedating - pharmacokinetics; Ileum - metabolism; Injections, Intravenous; levocetirizine; Male; Medical sciences; Muscle Contraction - drug effects; Muscle, Smooth - metabolism; pharmacokinetic–pharmacodynamic relationship; Pharmacology. Drug treatments; PHARMACY; Piperazines - administration & dosage; Piperazines - blood; Piperazines - pharmacokinetics; Pyrilamine - administration & dosage; Pyrilamine - pharmacokinetics; Receptors, Histamine H1 - metabolism; Research Papers; Tandem Mass Spectrometry; Time Factors; Tritium
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1038/sj.bjp.0707318

Background and purpose: The H1 receptor occupancy (H1RO) in brain is an indicator of central side effects of antihistamines. Here, we determined the kinetics of central and peripheral H1RO by levocetirizine in relation to its brain and plasma concentration, and investigated the role of the blood‐brain barrier in any delay in brain H1RO. Experimental approach: Concentration‐time profiles in plasma and brain were obtained after 0.1 and 1 mg kg−1 oral doses of levocetirizine in guinea pigs. H1RO in brain was measured ex vivo using [3H]‐mepyramine and, in the periphery, by measuring the degree of inhibition of histamine‐induced contractions of isolated guinea pig ileum. Key results: The concentration‐time profile of levocetirizine indicated lower levels (partition coefficient, Kp=0.06‐0.08), higher tmax (2‐4 h vs 1‐1.5 h) and longer terminal half‐life (4‐5.6 h vs 2.1‐2.8 h) in brain than plasma. The H1RO at 0.1 and 1 mg kg−1 were 75% and 97%, respectively, at 1 hr in the periphery and, in the brain, were