Peripheral and central H1 histamine receptor occupancy by levocetirizine, a non-sedating antihistamine; a time course study in the guinea pig.
OBJECTIVE
The H(1) 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.


METHODS
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.


RESULTS
The concentration-time profile of levocetirizine indicated lower levels (partition coefficient, K(p)=0.06-0.08), higher t(max) (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 <20% and 28-67% respectively, at all time points studied. Brain H1RO vs plasma concentrations profile showed a delay, but not when compared to brain concentrations.


CONCLUSIONS
This study demonstrates an effective peripheral antihistamine effect of levocetirizine without central adverse effects at the dose close to human therapeutic dose. The slow increase in H1RO in the brain with time was caused by slow blood-brain barrier transport of levocetirizine. This demonstrates the importance of measuring time course of brain H1RO in relation to brain concentrations of drugs.
Gupta
A
A
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Gillard
M
M
Christophe
B
B
Chatelain
P
P
Massingham
R
R
Hammarlund-Udenaes
M
M
D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D017332:Cetirizine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002744:Chlorpheniramine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006207:Half-Life; D039563:Histamine H1 Antagonists, Non-Sedating / Q000008:administration & dosage / Q000493:pharmacokinetics; D007082:Ileum / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011738:Pyrilamine / Q000008:administration & dosage / Q000493:pharmacokinetics; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014316:Tritium
D018926:Anti-Allergic Agents; D039563:Histamine H1 Antagonists, Non-Sedating; D010879:Piperazines; D011969:Receptors, Histamine H1; D014316:Tritium; D002744:Chlorpheniramine; C472067:levocetirizine; D011738:Pyrilamine; D017332:Cetirizine