Diphenhydramine pharmacokinetics after oral and intravenous administration of diphenhydramine and oral administration of dimenhydrinate to healthy dogs, and pharmacodynamic effect on histamine‐induced wheal formation: a pilot study

Abstract

Background -Histamine type-1 (H1) receptor antagonists such as diphenhydramine are frequently used for treatment of pruritus in dogs, yet therapeutic efficacy for allergic disorders is reported to be highly variable. Dimenhydrinate is a salt of diphenhydramine and 8-chlorotheophylline, and has been reported to produce superior oral absorption of diphenhydramine.Hypothesis/Objective -To determine the pharmacokinetic and pharmacodynamic properties of diphenhydramine in dogs after intravenous (1 mg/kg) and oral (5 mg/kg) administration, and when given orally as dimenhydrinate at a dose of 10 mg/kg (%5 mg/kg diphenhydramine).Animals -Each drug was administered to six healthy, fasted mixed-breed dogs in a research facility, using a cross-over design.Methods and materials -Blood samples were collected for pharmacokinetic analysis of diphenhydramine and chlorotheophylline at defined intervals. Pharmacodynamic response was measured by histamine-mediated cutaneous wheal formation.Results -There was great variability in the data and one dog was an extreme outlier. The mean systemic availabilities of diphenhydramine were 7.8% and 22.0% after oral administration of diphenhydramine and dimenhydrinate, respectively, whereas the mean maximum concentrations were 36 (AE 20) and 124 (AE 46) ng/mL. The terminal elimination half-lives of diphenhydramine and dimenhydrinate were 5.0 (AE 7.1) and 11.6 (AE 17.7) h, respectively. Plasma diphenhydramine concentrations did not correlate with the percentage reduction in histamine-induced wheal formation. Theophylline reached plasma concentrations considered to be therapeutic for dogs.

Pharmacokinetics of diphenhydramine following single‐dose intravenous and oral administration in non‐fasted adult horses

“…This substantial variability demonstrates the difficulty when extrapolating doses across species. Based on our results, horses appear to reach peak plasma concentrations of diphenhydramine more rapidly than dogs, but this may relate to IG versus oral administration, or differences in postprandial timing of drug administration (Ehling et al, 2019). Despite a shorter T max , bioavailability was low for both IG doses in horses, and current information suggests that oral administration of diphenhydramine at 5 mg/kg or less is unlikely to lead to therapeutic effect in adult horses.…”

“…This substantial variability demonstrates the difficulty when extrapolating doses across species. Based on our results, horses appear to reach peak plasma concentrations of diphenhydramine more rapidly than dogs, but this may relate to IG versus oral administration, or differences in postprandial timing of drug administration (Ehling et al, 2019).…”

“…Peak plasma concentrations of diphenhydramine after oral administration in humans are reported to occur at two to 3 h with bioavailability ranging from 42 to 61% (Paton & Webster, 1985). In dogs, a similarly monogastric species, peak concentrations after oral diphenhydramine administration were achieved between 1 and 4 h (Ehling et al, 2019; Koyanagi et al, 2014) with bioavailability below 8% (Ehling et al, 2019; Koyanagi et al, 2014). This substantial variability demonstrates the difficulty when extrapolating doses across species.…”

Pharmacotherapy of canine atopic dermatitis - current state and new trends

“…In dogs, diphenhydramine (p.os 2-5 mg/kg 1-2x daily) or chlorphenamine (p.os 4-8 mg/kg 2-3x daily) are used. Diphenhydramine might not work in the recommended doses, as we did not see an inhibition of histamine-induced weal or flare reactions in laboratory dogs (11). For hydroxyzine, a reliable PK/PD modelling exists for histamine and anti-IgE induced skin reactions.…”

Association of Veterinary Hematology and Transfusion Medicine (AVHTM) transfusion reaction small animal consensus statement (TRACS). Part 3: Diagnosis and treatment

“…There are no randomized controlled trials in people or animals evaluating the efficacy of antihistamines in the treatment of cutaneous allergic transfusion reactions. One experimental canine study (LOE 3, fair) suggests cetrazidine may be of use in allergic reactions caused by a non‐blood product trigger 50 but another similar study (LOE 3, Fair) found no benefit in the use of diphenhydramine 51 . However, both studies looked solely at the drugs’ effects on cutaneous wheal formation and not pruritus.…”