Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans

Abstract

Absorption, distribution, metabolism and excretion of desloratadine, fexofenadine, levocetirizine, and mizolastine in humans have been compared. The time required to reach peak plasma levels (tmax) is shortest for levocetirizine (0.9 h) and longest for desloratadine (> or =3 h). Steady-state plasma levels are attained after about 6 days for desloratadine, 3 days for fexofenadine, 2-3 days for mizolastine and by the second day for levocetirizine. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg) and mizolastine (1-1.2 L/kg), larger for fexofenadine (5.4-5.8 L/kg) and particularly large for desloratadine (approximately 49 l/kg). Fexofenadine and levocetirizine appear to be very poorly metabolized (approximately 5 and 14% of the total oral dose, respectively). Desloratadine and mizolastine are extensively metabolized. After administration of 14C-levocetirizine to healthy volunteers, 85 and 13% of the radioactivity are recovered in urine and faeces, respectively. In contrast, faeces are the preferential route of excretion for 14C-fexofenadine (80% vs. 11% of the radioactive dose in urine). The corresponding values are 41% (urine) and 47% (faeces) for 14C-desloratadine, 84-95% (faeces) and 8-15% (urine) for 14C-mizolastine. The absolute bioavailability is 50-65% for mizolastine; it is high for levocetirizine as the percentage of the drug eliminated unchanged in the 48 h urine is 77% of the oral dose; the estimation for fexofenadine is at least 33%; no estimation was found for desloratadine. Fexofenadine is a P-glycoprotein (P-gp) substrate and P-gp is certainly involved both in the poor brain penetration by the compound and, at least partially, in a number of observed drug interactions. An interaction of desloratadine with P-gp has been suggested in mice, whereas the information on mizolastine is very poor. The fact that levocetirizine is a substrate of P-gp, although weak in an in vitro model, could contribute to prevent drug penetration into the brain, whereas it is unlikely to be of any clinical relevance for P-gp-mediated drug interactions.

Modern approaches to therapy of allergic rhinosinusitis

“…Данная группа пре-паратов, помимо блокады гистаминовых рецепторов, оказывают антагонистическое действие в отношении медиаторов воспаления, подавляют привлечение эозино-филов в очаг воспаления. Таким образом, данные лекар-ственные средства обеспечивают подавление опосредо-ванных гистамином симптомов (зуд в носу, симптомы конъюнктивита, ринорея, чихание), тем самым значитель-но повышают качество жизни пациентов с аллергическим риносинуситом [1,13].…”

“…Следовательно, препарат можно принимать как после еды, так и натощак. Метаболизм и выведение пре-парата не зависят от возраста и пола больного [13][14][15].…”

Pharmacology of Antihistamines

“…Third, and probably most influential, is the apparent volume of distribution which determines the plasma concentration of a drug after complete body distribution. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg), larger for fexofenadine (5.4-5.8 L/kg), and particularly large for desloratadine (~49 L/kg)[32]. The large apparent volume of distribution of desloratadine is largely due to its extensive intracellular uptake.…”

“…The metabolism and elimination of H 1 -antihistamines have been extensively reviewed elsewhere[32,49] and will be only briefly summarized here. Cetirizine and levocetirizine are not metabolized and are excreted primarily unchanged in the urine[32].…”

“…Cetirizine and levocetirizine are not metabolized and are excreted primarily unchanged in the urine[32]. Desloratadine undergoes extensive metabolism in the liver.…”