Clinical Pharmacokinetics

, Volume 21, Issue 5, pp 372–393

Pharmacokinetic Optimisation of Histamine H1-Receptor Antagonist Therapy

  • F. Estelle
  • R. Simons
  • Keith J. Simons
Review Article Pharmacokinetics-Therapeutics

DOI: 10.2165/00003088-199121050-00005

Cite this article as:
Estelle, F., Simons, R. & Simons, K.J. Clin. Pharmacokinet. (1991) 21: 372. doi:10.2165/00003088-199121050-00005


Second-generation, relatively nonsedating histamine H1-receptor antagonists (H1-RA) are extensively used worldwide for the symptomatic treatment of allergic rhinoconjunctivitis and chronic urticaria. Information about the pharmacokinetics and pharmacodynamics of these medications, while still incomplete, is now sufficient to permit optimisation of therapy. Published pharmacokinetic and pharmacodynamic information on these H1-RA is summarised here, and areas where more data are required are delineated.

Serum concentrations of most second-generation H1-RA are relatively low, and are usually measured by radioimmunoassay. After oral administration, peak concentrations are observed within 2 or 3h. Bioavailability has not been well studied, due to the lack of intravenous formulations. Most H1-RA are metabolised in the hepatic cytochrome P450 system: terfenadine, astemizole, loratadine, azelastine, and ebastine have 1 or more active metabolites which are present in serum in higher concentrations than the respective parent compound, and therefore can be measured by high performance liquid chromatography. Cetirizine, an active metabolite of the first generation H1-receptor antagonist hydroxyzine, is not further metabolised to any great extent in vivo, and is eliminated via renal excretion. Levocabastine is also eliminated primarily by excretion.

Serum elimination half-life values differ greatly from 1 H1-RA to another, and are 24h or less for terfenadine, astemizole, loratadine, cetirizine, azelastine and ebastine, and the active metabolites of terfenadine, loratadine and ebastine. The active metabolite of azelastine (demethyl-azelastine) has a serum elimination half-life value of about 2 days, while that of astemizole (demethyl-astemizole) has a value of 9.5 days. From the few published studies in which the apparent volumes of distribution of the second-generation H1-RA have been calculated, it appears that tissue distribution is extensive.

In children, the half-lives of H1-RA are generally shorter than are found in adults; there is no published information on the pharmacokinetics of astemizole, loratadine, azelastine, or ebastine in children. In some elderly adults, terfenadine, loratadine and cetirizine may have longer half-lives than in young healthy adults. There is little published data on the pharmacokinetics of the second-generation H1-RA in patients with impaired hepatic function. The half-life of cetirizine is prolonged in those with impaired renal function. There is a paucity of information on the pharmacokinetics of H1-RA in neonates, in pregnancy or during lactation.

Potential drug interactions between H1-RA and central nervous system-active substances such as alcohol and diazepam, although well studied clinically, have not been studied adequately from a pharmacokinetic standpoint. Moreover, there are few pharmacokinetic investigations of drug interactions between the second-generation H1-RA and decongestants, with which they are marketed in fixed-dose combinations.

The H1-RA, because of their ability to suppress the histamine- or antigen-induced wheal and flare response in the skin, can be studied pharmacodynamically in a highly objective manner; however, while efficacy studies are numerous, there are not many true pharmacodynamic studies in which the antihistaminic effect is correlated with serum drug concentrations. The duration of action of a single manufacturer’s recommended dose of most second-generation H1-RA is 24h or more; therefore, despite their differing pharmacokinetic profiles, these medications are suitable for once-daily administration.

In the past 10 years, important pharmacokinetic and pharmacodynamic information about H1-RA has become available, facilitating the optimisation of treatment with these medications. Further studies are required, particularly in unique patient populations such as children, elderly patients and patients with hepatic failure, and with regard to the interrelationships of the pharmacokinetics and pharmacodynamics of H1-RA, and the pharmacokinetic interactions between H1-RA and other medications with which they are commonly administered.

Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • F. Estelle
    • 1
  • R. Simons
    • 1
  • Keith J. Simons
    • 1
  1. 1.Faculty of Medicine, and Faculties of Pharmacy, Medicine and ScienceUniversity of ManitobaWinnipegCanada
  2. 2.Children’s Hospital of WinnipegWinnipegCanada

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