Pharmacodynamics
Cetirizine acts as a highly selective antagonist of the histamine H1 receptor.[24] The Ki values for the H1 receptor are approximately 6 nM for cetirizine, 3 nM for levocetirizine, and 100 nM for dextrocetirizine, indicating that the levorotatory enantiomer is the main active form.[24] Cetirizine 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.[24] 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.[25][26] It shows negligible inhibition of the hERG channel (IC50 > 30 μM)[27] and no cardiotoxicity has been observed with cetirizine at doses of up to 60 mg/day, six times the normal recommended dose[24] and the highest dose of cetirizine that has been studied in healthy subjects.[28]
Cetirizine crosses the blood–brain barrier only slightly, and for this reason, produces minimal sedation compared to many other antihistamines.[29] A positron emission tomography (PET) study found that brain occupancy of the H1 receptor was 12.6% for 10 mg cetirizine, 25.2% for 20 mg cetirizine, and 67.6% for 30 mg hydroxyzine.[30] (A 10 mg dose of cetirizine equals about a 30 mg dose of hydroxyzine in terms of peripheral antihistamine effect.)[31] 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.[32] In accordance, H1 receptor occupancy correlated well with subjective sleepiness for 30 mg hydroxyzine but there was no correlation for 10 or 20 mg cetirizine.[30] As such, brain penetration and brain H1 receptor occupancy by cetirizine are dose-dependent, and in accordance, while cetirizine 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.[30]
Cetirizine also shows anti-inflammatory properties independent of H1 receptors.[33] 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.[34][35][36][37][38] It has been shown to inhibit eosinophil chemotaxis and LTB4 release.[39] 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
Cetirizine is rapidly and extensively absorbed upon oral administration in tablet or syrup form.[24] The oral bioavailability of cetirizine is at least 70% and of levocetirizine is at least 85%.[7] The Tmax of cetirizine is approximately 1.0 hour regardless of formulation. The pharmacokinetics of cetirizine have been found to increase linearly with dose across a range of 5 to 60 mg.[24] Its Cmax following a single dose has been found to be 257 ng/mL for 10 mg and 580 ng/mL for 20 mg.[40] Food has no effect on the bioavailability of cetirizine 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%.[24]
Absorption
Cetirizine is rapidly and extensively absorbed upon oral administration in tablet or syrup form.[24] The oral bioavailability of cetirizine is at least 70% and of levocetirizine is at least 85%.[7] The Tmax of cetirizine is approximately 1.0 hour regardless of formulation. The pharmacokinetics of cetirizine have been found to increase linearly with dose across a range of 5 to 60 mg.[24] Its Cmax following a single dose has been found to be 257 ng/mL for 10 mg and 580 ng/mL for 20 mg.[40] Food has no effect on the bioavailability of cetirizine 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%.[24][40]
Distribution
The mean plasma protein binding of cetirizine has been found to be 93 to 96% across a range of 25 to 1,000 ng/mL independent of concentration.[40] Plasma protein binding of 88 to 96% has also been reported across multiple studies.[7] The drug is bound to albumin with high affinity, while α1-acid glycoprotein and lipoproteins contribute much less to total plasma protein binding.[7] The unbound or free fraction of levocetirizine has been reported to be 8%.[7] The true volume of distribution of cetirizine is unknown but is estimated to be 0.3 to 0.45 L/kg.[24][7] Cetirizine poorly and slowly crosses the blood–brain barrier
Cetirizine is notably not metabolized by the cytochrome P450 system.[45] 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.[24] Studies with cetirizine synthesized with radioactive carbon-14 show that 90% of excreted cetirizine is unchanged at 2 hours, 80% at 10 hours, and 70% at 24 hours, indicating limited and slow metabolism.[40] While cetirizine 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.[24][40] The precise enzymes responsible for
Elimination
Cetirizine is eliminated approximately 70 to 85% in the urine and 10 to 13% in the feces.[24] In total, about 60% of cetirizine eliminated in the urine is unchanged.[24][40] It is eliminated in the urine via an active transport mechanism.[40] The elimination half-life of cetirizine ranges from 6.5 to 10 hours in healthy adults, with a mean across studies of approximately 8.3 hours.[24][40] The elimination half-life of cetirizine is increased in the elderly (to 12 hours), in hepatic impairment (to 14 hours), and in renal impairment (to 20 hours).[40]
