The advantages for an H1 antihistamine of a low volume of distribution

With a few exceptions, antihistamines are rapidly and completely absorbed after oral administration, peak plasma concentrations being reached after 1±4 h. However, the plasma concentration of antihistamines after recommended doses is highly variable as a result of differences in metabolism and tissue distribution. The method used to de®ne the basis for a new classi®cation of a well-known pharmacologic class requires the selection of drugs according to their respective potencies. However, in the case of the H1 antagonists, many drugs in current use, particularly those belonging to the second generation of antihistamines, are already well recognized as very effective treatments in allergy-based diseases. Since these drugs are often used to treat nonlife-threatening conditions such as allergic rhinitis, consideration of their bene®t/risk ratio is of great importance (1, 2). Therefore, progress with this class of drugs might involve not only an increase in ef®cacy but also improvements in their safety and speci®city. In pharmacokinetic terms, it is desirable for any drug to have the lowest volume of distribution (VD) compatible with the therapeutic goal of interacting with the target receptors at effective concentrations, while avoiding organs where the drug is ineffective or toxic. Many drugs available today are extensively distributed throughout all the organs of the body. This is because they are liposoluble, a feature which, together with nonionization, is a prerequisite for tissue transfer by passive diffusion after oral administration. Liposolubility does not result in any selectivity of organ transfer and in fact permits passive diffusion across almost all cell membranes. Consequently, the distribution of a drug is often greater than necessary for its therapeutic effect, with the potential to lose a signi®cant part of its activity. This is especially true of those H1 antagonists which are metabolized by the liver. It can be seen that the optimal distribution of a drug should be the lowest which provides the amount of the drug necessary to reach the selected receptor effectively while avoiding organs where the drug is useless or toxic. A low VD can be de®ned as that smaller than the volume of exchangeable water in the body which is freely and quickly exchanged between extracellular ̄uids and cytosol; this concept is illustrated in Fig. 1. Evaluation with antipyrine has shown the volume of exchangeable water to be 0.6 l/kg (3). Exchangeable water in the body includes the plasma volume, interstitial ̄uids, and the water in equilibrium with extracellular ̄uids and cytosol. A lower VD than that of exchangeable water in the body means that the drug may not be uniformly distributed in the body ̄uids and consequently will be retained in one of its components. The intermixture of free and bound forms will result in partial restrictive distribution with an overall VD of 0.6±0.1 l/kg. When a drug is almost completely bound to human serum albumin (HSA), its VD is superimposable on that of its binding protein; 0.1 l/kg for HSA. Conversely, a higher VD than 0.6 l/kg indicates that the drug can not only diffuse throughout the exchangeable water but also bind to cellular structures. A low VD may represent a distinct advantage for a H1 antagonist, as it would optimize the body distribution to the lone targeted receptors and minimize the potential to cross the blood±brain barrier. H1 receptors have a wide cellular distribution, being found on smooth-muscle cells, endothelial cells, and eosinophils; antihistamines exert their effects by competing with histamine for occupancy of these receptors (4). In man, the H1 receptors of the brain are numerous, constituting about 40% of the total amount of H1 Allergy 2000: 55: 17±21 Printed in UK. All rights reserved Copyright # Munksgaard 2000