L-Stereoisomer, levocetirizine (top) and D-stereoisomer of<unk> . Pharmacodynamics<unk>  acts as a highly selective antagonist of the histamine H1 receptor. The Ki values for the H1 receptor are approximately 6 nM for<unk> , 3 nM for levocetirizine, and 100 nM for dextrocetirizine, indicating that the levorotatory enantiomer is the main active form.<unk>  has 600-fold or greater selectivity for the H1 receptor over a wide variety of other sites, including muscarinic acetylcholine, serotonin, dopamine, and α-adrenergic receptors, among many others. The drug shows 20,000-fold or greater selectivity for the H1 receptor over the five muscarinic acetylcholine receptors, and hence does not exhibit anticholinergic effects. It shows negligible inhibition of the hERG channel ( > 30 μM) and no cardiotoxicity has been observed with<unk>  at doses of up to 60 mg/day, six times the normal recommended dose and the highest dose of<unk>  that has been studied in healthy subjects.<unk>  crosses the blood-brain barrier only slightly, and for this reason, produces minimal sedation compared to many other antihistamines. A positron emission tomography (PET) study found that brain occupancy of the H1 receptor was 12.6% for 10 mg<unk> , 25.2% for 20 mg<unk> , and 67.6% for 30 mg hydroxyzine. (A 10 mg dose of<unk>  equals about a 30 mg dose of hydroxyzine in terms of peripheral antihistamine effect.) PET studies with antihistamines have found that brain H1 receptor occupancy of more than 50% is associated with a high prevalence of somnolence and cognitive decline, whereas brain H1 receptor occupancy of less than 20% is considered to be non-sedative. In accordance, H1 receptor occupancy correlated well with subjective sleepiness for 30 mg hydroxyzine but there was no correlation for 10 or 20 mg<unk> . As such, brain penetration and brain H1 receptor occupancy by<unk>  are dose-dependent, and in accordance, while<unk>  at doses of 5 to 10 mg have been reported to be non-sedating or mildly sedating, a higher dose of 20 mg has been found to induce significant drowsiness in other studies.<unk>  also shows anti-inflammatory properties independent of H1 receptors. The effect is exhibited through suppression of the NF-κB pathway, and by regulating the release of cytokines and chemokines, thereby regulating the recruitment of inflammatory cells. It has been shown to inhibit eosinophil chemotaxis and LTB4 release. At a dosage of 20 mg, Boone et al. found that it inhibited the expression of VCAM-1 in patients with atopic dermatitis. Pharmacokinetics Absorption<unk>  is rapidly and extensively absorbed upon oral administration in tablet or syrup form. The oral bioavailability of<unk>  is at least 70% and of levocetirizine is at least 85%. The Tmax of<unk>  is approximately 1.0 hour regardless of formulation. The pharmacokinetics of<unk>  have been found to increase linearly with dose across a range of 5 to 60 mg. Its Cmax following a single dose has been found to be 257 ng/mL for 10 mg and 580 ng/mL for 20 mg. Food has no effect on the bioavailability of<unk>  but has been found to delay the Tmax by 1.7 hours (i.e., to approximately 2.7 hours) and to decrease the Cmax by 23%. Similar findings were reported for levocetirizine, which had its Tmax delayed by 1.25 hours and its Cmax decreased by about 36% when administered with a high-fat meal. Steady-state levels of<unk>  occur within 3 days and there is no accumulation of the drug with chronic administration. Following once-daily administration of 10 mg<unk>  for ten days, the mean Cmax was 311 ng/mL. Distribution The mean plasma protein binding of<unk>  has been found to be 93 to 96% across a range of 25 to 1,000 ng/mL independent of concentration. Plasma protein binding of 88 to 96% has also been reported across multiple studies. The drug is bound to albumin with high affinity, while α1-acid glycoprotein and lipoproteins contribute much less to total plasma protein binding. The unbound or free fraction of levocetirizine has been reported to be 8%. The true volume of distribution of<unk>  is unknown but is estimated to be 0.3 to 0.45 L/kg.<unk>  poorly and slowly crosses the blood-brain barrier, which is due mainly to its chemical properties but also to a minor extent to its activity as a P-glycoprotein substrate. Metabolism<unk>  does not undergo extensive metabolism. It is notably not metabolized by the cytochrome P450 system. Because of this, it does not interact significantly with drugs that inhibit or induce cytochrome P450 enzymes such as theophylline, erythromycin, clarithromycin, cimetidine, or alcohol. While<unk>  does not undergo extensive metabolism or metabolism by the cytochrome P450 enzyme, it does undergo some metabolism by other means, the metabolic pathways of which include oxidation and conjugation. Plasma radioactivity attributed to unchanged<unk>  is more than 90% at 2 hours, 80% at 10 hours, and 70% at 24 hours, indicating limited and slow metabolism. The enzymes responsible for transformation of<unk>  have not been identified. Elimination<unk>  is eliminated approximately 70 to 85% in the urine and 10 to 13% in the feces. About 50 or 60% of<unk>  eliminated in the urine is unchanged. It is eliminated in the urine via an active transport mechanism. The elimination half-life of<unk>  ranges from 6.5 to 10 hours in healthy adults, with a mean across studies of approximately 8.3 hours. Its duration of action is at least 24 hours. The elimination half-life of<unk>  is increased in the elderly (to 12 hours), in hepatic impairment (to 14 hours), and in renal impairment (to 20 hours).
Cetirizine
Meclizine
Budesonide
Levocetirizine
Fexofenadine
Chloropyramine
Terfenadine
Ibuprofen