Comparison of pharmacodynamic variables following oral versus transdermal administration of atenolol to healthy cats.
ABSTRACT To describe the disposition of and pharmacodynamic response to atenolol when administered as a novel transdermal gel formulation to healthy cats.
7 healthy neutered male client-owned cats.
Atenolol was administered either orally as a quarter of a 25-mg tablet or as an equal dose by transdermal gel. Following 1 week of treatment, an ECG and blood pressure measurements were performed and blood samples were collected for determination of plasma atenolol concentration at 2 and 12 hours after administration.
2 hours after oral administration, 6 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 579 +/- 212 ng/mL. Two hours following transdermal administration, only 2 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 177 +/- 123 ng/mL. The difference in concentration between treatments was significant. Trough plasma atenolol concentrations of 258 +/- 142 ng/mL and 62.4 +/- 17 ng/mL were achieved 12 hours after oral and transdermal administration, respectively. A negative correlation was found between heart rate and plasma atenolol concentration.
Oral administration of atenolol at a median dose of 1.1 mg/kg every 12 hours (range, 0.8 to 1.5 mg/kg) in cats induced effective plasma concentrations at 2 hours after treatment in most cats. Transdermal administration provided lower and inconsistent plasma atenolol concentrations. Further studies are needed to find an effective formulation and dosing scheme for transdermal administration of atenolol.
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ABSTRACT: Analysis of heart rate (HR) and heart rate variability (HRV) are powerful tools to investigate cardiac diseases, but current methods, including 24-h Holter monitoring, can be cumbersome and may be compromised by movement artefact. A commercially available data capture and analysis system was used in anaesthetised healthy cats to measure HR and HRV during pharmacological manipulation of HR. Seven healthy cats were subjected to a randomised crossover study design with a 7day washout period between two treatment groups, placebo and atenolol (1mg/kg, IV), with the efficacy of atenolol to inhibit β1 adrenoreceptors challenged by epinephrine. Statistical significance for the epinephrine challenge was set at P<0.0027 (Holm-Bonferroni correction), whereas a level of significance of P<0.05 was set for other variables. Analysis of the continuous electrocardiography (ECG) recordings showed that epinephrine challenge increased HR in the placebo group (P=0.0003) but not in the atenolol group. The change in HR was greater in the placebo group than in the atenolol group (P=0.0004). Therefore, compared to cats pre-treated with placebo, pre-treatment with atenolol significantly antagonised the tachycardia while not significantly affecting HRV. The increased HR in the placebo group following epinephrine challenge was consistent with a shift of the sympathovagal balance towards a predominantly sympathetic tone. However, the small (but not significant at the critical value) decrease in the normalised high-frequency component (HFnorm) in both groups of cats suggested that epinephrine induced a parasympathetic withdrawal in addition to sympathetic enhancement (increased normalised low frequency component or LFnorm). In conclusion, this model is a highly sensitive and repeatable model to investigate HRV in anaesthetised cats that would be useful in the laboratory setting for short-term investigation of cardiovascular disease and subtle responses to pharmacological agents in this species.The Veterinary Journal 11/2013; 199(2). DOI:10.1016/j.tvjl.2013.11.006 · 2.17 Impact Factor
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ABSTRACT: Abstract AIM: To determine the pharmacokinetics of a novel lipophilic formulation of transdermal methimazole compared to oral carbimazole. Healthy cats received 5 mg carbimazole orally every 12 hours for 13 treatments (n=6), then received transdermal methimazole (n=5) at a dose of 5 mg, then 10 mg, once daily, on the pinna for seven days, with 21 days between treatments. Concentrations of methimazole in serum over 24 hours and at 148 hours were determined by high performance liquid chromatography. Concentrations of methimazole in serum for the first 24 hours were not reliably detected in all cats treated with 5 mg methimazole transdermally, while for those receiving 5 mg carbimazole orally and 10 mg methimazole transdermally all cats had detectable concentrations of methimazole in serum. The maximum concentration and area under the curve were lower in cats receiving 10 mg methimazole transdermally (108 (SD 25) ng/mL and 2544 (SD 216) mg-hour/mL, respectively) than those receiving 5 mg oral carbimazole (355 (SD 113) ng/mL and 31866 (SD 439) ng-hour/mL, respectively) (p<0.05). The time at maximal concentration and elimination half-life were longer for 10 mg transdermal methimazole (5.2 (SD 1.1) hours and 13 (SD 3) hours, respectively) compared to 5 mg oral carbimazole (2.1 (SD 1.6) hours and 5.1 (SD 1.2) hours, respectively). At 148 hours, mean concentrations of methimazole in serum were higher in cats receiving 10 mg methimazole transdermally (506 (SD 165) ng/mL) than for 5 mg oral carbimazole (255 (SD 28) ng/mL) or 5 mg transdermally (204 (SD 76) ng/mL). The mean relative bioavailability of 10 mg transdermal methimazole compared to oral carbimazole was 50 (min 43, max 63)%. Transdermal methimazole at a dose of 10 mg administered to the pinnae of healthy cats once daily in a novel lipophilic formulation has half the relative bioavailablity compared to 5 mg oral carbimazole. Transdermal methimazole can be absorbed from the skin of healthy cats.New Zealand veterinary journal 12/2013; DOI:10.1080/00480169.2013.875990 · 1.22 Impact Factor
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ABSTRACT: The use of transdermal medications in cats has become popular in veterinary medicine due to the ease of administration compared to oral medication. However, the research to support systemic absorption of drugs applied to the pinna after transdermal administration in cats is limited. The aim of this study was to characterize the percutaneous absorption pharmacokinetics of methimazole in a lipophilic vehicle compared to methimazole in Pluronic(®) lecithin organogel (PLO) using a finite dose applied to feline ear skin in an in vitro Franz cell model. The two formulations of methimazole (10 mg) were applied to the inner stratum corneum of six pairs of feline ears. The receptor medium was sampled up to 30 h post-administration, and methimazole concentrations were measured using high-performance liquid chromatography (HPLC). Histological examination of all ears was undertaken as small differences in the thickness of ear skin may have contributed to inter-individual differences in methimazole absorption between six cats. Methimazole was absorbed more completely across the pinnal skin when administered in the lipophilic vehicle compared to administration in the PLO gel (P < 0.001). © 2015 John Wiley & Sons Ltd.Journal of Veterinary Pharmacology and Therapeutics 02/2015; DOI:10.1111/jvp.12213 · 1.32 Impact Factor