Blood distribution of levocetirizine, a new non‐sedating histamine H₁‐receptor antagonist, in humans

Abstract

The aim of the present study was to determine (1) the extent of levocetirizine binding to human blood cells, plasma and individual plasma proteins; (2) the parameters for levocetirizine binding to individual plasma proteins both at their physiological concentrations and, for human serum albumin (HSA), at a lower saturating concentration; and (3) to simulate levocetirizine distribution in human blood using the information obtained at physiological haematocrit (H) for blood cells and at physiological concentrations for individual plasma proteins. The nature of the main binding sites of HSA, i.e. site I (warfarin) and site II (diazepam), preferentially involved in levocetirizine binding was also investigated. Over the range of therapeutic concentrations and multiples thereof, levocetirizine is extensively bound to blood components, the free fraction remaining constant (6.45%) and the fraction bound to blood cells and to plasma proteins accounting for 27.43 and 66.11%, respectively. The binding of levocetirizine to HSA in the presence of physiological concentrations of non-esterified fatty acids (NEFAs) is the main interaction of levocetirizine in blood (50.68% of overall blood binding). This interaction is fatty acid sensitive, with decreasing concentrations of NEFA increasing the amount of bound drug and vice versa. Levocetirizine is also bound to alpha1-acid-glycoprotein and high-density lipoproteins (5.17 and 6.89% of overall blood binding, respectively). The displacement of levocetirizine by diazepam is consistent with the binding of this drug to HSA at site II, as diazepam is a specific marker for this site. The binding of levocetirizine to HSA at site II being characterized by a low association constant, other drugs sharing the same site with high association constants cannot displace levocetirizine except at very high plasma concentrations. In any case, at therapeutic concentrations of levocetirizine and at physiological protein concentrations, the observation that none of the levocetirizine binding proteins is saturated suggests that very little or no variation of the free fraction will occur although a different distribution of its bound forms is possible.

Stereoselective pharmacokinetics of cetirizine in the guinea pig: role of protein binding

“…The f u of 8% for R-CZE in human plasma determined in the present study is comparable to the binding reported previously [7]. The lower f u of 5% for R-CZE determined by Benedetti et al could be because of the different technique used [6].…”

“…Benedetti et al showed that, at concentrations ranging from 0.2 to 1 mg/ml, the percentage of bound R-CZE was concentration independent (94.8-95.5%) [6]. Bree et al also reported high binding (91.2 AE 0.66%) of R-CZE to human plasma over the concentration range studied (0.21-4.98 mm) [7]. CZE binding to the whole serum was reported to be 88-89% by Pagliara et al [8] and plasma binding of 88-90% by Tillement [9].…”

“…Since CZE is a low extraction ratio drug and both the clearance and volume of distribution of R-CZE are lower than S-CZE in humans, it is plausible that protein binding plays a role in the stereoselective pharmacokinetics of CZE. Plasma protein binding of R-CZE and CZE in humans has been studied [6][7][8][9]. Benedetti et al showed that, at concentrations ranging from 0.2 to 1 mg/ml, the percentage of bound R-CZE was concentration independent (94.8-95.5%) [6].…”

BRAIN DISTRIBUTION OF CETIRIZINE ENANTIOMERS: COMPARISON OF THREE DIFFERENT TISSUE-TO-PLASMA PARTITION COEFFICIENTS: Kp, Kp,u, AND Kp,uu

“…Similar results from the two techniques indicated that the higher f u of CZE enantiomers reflects the in vivo situation. The main interaction of CZE in blood is binding to albumin (Bree et al, 2002). It is known that the acute phase reaction in the disease state and injury leads to hypoalbuminemia (Fleck et al, 1985;Sjunnesson et al, 2001).…”

Development of New H1 Antihistamines: The Importance of Pharmacokinetics in the Evaluation of Safe and Therapeutically Effective Agents

“…Levocetirizine and cetirizine have the lowest volumes of distribution at 0.4-0.5 L/Kg, higher than the volume of extra cellular water but inferior to that of total body water [17,39]. The H1 antihistamines display a moderate (fexofenadine) to high (loratadine, mizolastine) protein binding [21,24,31,39,37,40].…”