Pharmacokinetics of the cytochrome P‐450 substrates phenytoin, theophylline, and diazepam in healthy Greyhound dogs

KuKanich, Butch; Nauss, Jon L

doi:10.1111/j.1365-2885.2011.01316.x

Cited by 11 publications

(11 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Noncompartmental analysis was used to estimate PK parameters for both the total and unbound PHT for each dog individually (Table ). The elimination half‐life of total PHT ranged from 2.8 to 3.6 h with the half‐life of the unbound more variable ranging from 1.9 to 5.4 h, which agrees with previously published literature …”

Section: Resultssupporting

confidence: 91%

“…The elimination half-life of total PHT ranged from 2.8 to 3.6 h with the half-life of the unbound more variable ranging from 1.9 to 5.4 h, which agrees with previously published literature. 11,12 PHT compartmental PK analysis One-, two-, and three-compartment structural models were evaluated. Generally, both the unbound and total PHT concentration-time curves were best fit by a two-compartment model (Fig.…”

Section: Pht Protein Binding and Noncompartmental Pk Analysismentioning

confidence: 99%

See 1 more Smart Citation

Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus

et al. 2015

View full text Add to dashboard Cite

SUMMARYObjective: Canine status epilepticus (CSE) has potential as a translational platform to evaluate the safety and efficacy of novel compounds and inform human status epilepticus trials. The aim of this study was to determine the intravenous dose of fosphenytoin (FOS) needed for dogs in a CSE clinical trial to attain phenytoin (PHT) concentrations similar to those used for human status epilepticus and monitor PHT concentrations. Methods: Four healthy dogs were used to characterize PHT pharmacokinetics. Each received either 15 mg/kg or 25 mg/kg of PHT equivalent intravenously. Blood samples were collected and FOS (total) and derived PHT (total and unbound) plasma concentrations were measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Noncompartmental pharmacokinetics (PK) parameter values were determined and compartmental PK modeling and simulations were used to select the dose for the clinical trial with a target goal of 1-2 lg/ml unbound PHT at 30-60 min postinfusion. Predicted total and unbound PHT concentrations were compared with concentrations in blood collected from dogs treated for CSE in the clinical trial. Results: Initial estimates suggested that a loading dose of 25 mg/kg would attain unbound concentrations of 1-2 lg/ml; however, this dose produced concentrations above 3-6 lg/ml, which resulted in clinically significant toxicity. A two-compartment model best fit the PHT concentration data with alpha-phase half-life of 2-5 min and elimination half-life of~5 h. Based on the simulations, a dose of 15 mg/kg was selected and used in the clinical trial and 15 of 16 dogs randomized to the treatment arm had PHT plasma concentrations within the goal range. Significance: This study demonstrates that characterization of pharmacokinetics in a small number of dogs is useful in determining dosage regimens designed to attain targeted concentrations in clinical trials. Using this approach, we were able to determine a safe and effective dose of FOS for a clinical trial of CSE.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Pht Protein Binding and Noncompartmental Pk Analysismentioning

confidence: 99%

Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus

et al. 2015

View full text Add to dashboard Cite

show abstract

“…It has been hypothesized that the short t 1/2,β of rapid release theophylline initially reported (McKiernan et al, ) may actually be due to genetic homogeneity of drug metabolizing enzymes among the purpose‐bred animals used in that study rather than the drug formulation (Bach et al, ; KuKanich & Nauss ). Pharmacokinetics of intravenous theophylline in Greyhounds and in a mixed patient population have demonstrated longer terminal t 1/2 (8.4–9.2 hr) compared to purpose‐bred animals (5.7 hr), supporting a difference in clearance rather than absorption of different formulations (Bach et al, ; KuKanich & Nauss , McKiernan et al, ). The long t 1/2 of intravenous aminophylline in our mixed population was 7.52 ± 1.18 hr, providing further evidence for this theory.…”

Section: Discussionmentioning

confidence: 97%

Pharmacokinetics of a modified, compounded theophylline product in dogs

Cavett

McKiernan

et al. 2019

Vet Pharm & Therapeutics

View full text Add to dashboard Cite

Theophylline is a commonly used bronchodilator drug for treatment of chronic canine bronchitis, but no formulations validated in dogs are currently available. An oral, modified and compounded theophylline product (MCT), which could fulfil this need, is available through a USP‐compliant, veterinary compounding pharmacy; however, its pharmacokinetic properties are unknown. The aim of this study was to determine the pharmacokinetics of MCT. Plasma drug concentrations were measured in seven healthy, fed dogs after single doses of intravenous aminophylline (8.6 mg/kg theophylline equivalent) and oral MCT (10 mg/kg). Systemic bioavailability of the MCT was 96.2 ± 32.9%. MCT times to maximum concentration, mean absorption time and terminal half‐life were 8.85 ± 3.63, 6.95 ± 3.42, and 8.67 ± 1.62 hr, respectively. Based on simulations of 10 mg/kg and 12‐hr dosing, steady‐state plasma theophylline concentrations are expected to exceed the minimum therapeutic concentration for 71.7 ± 35.6% of the dosing interval. Overall, the MCT product investigated showed similar pharmacokinetic characteristics compared to previously validated extended‐release theophylline products. An oral dose of 10 mg/kg q 12 hr is likely an appropriate dosage to begin therapy; however, therapeutic drug monitoring may be warranted because of inter‐individual variation.

show abstract

“…; Zoran et al. ; KuKanich & Nauss ). If a pattern of decreased clearance similar to that of thiobarbiturates and propofol were to occur with amitriptyline, then Greyhounds would be expected to show much higher oral bioavailability than other dog breeds as a result of a lower first pass metabolism effect.…”

Section: Discussionmentioning

confidence: 98%

Pharmacokinetics of intravenous and oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs

Norkus

Rankin

KuKanich

2015

Veterinary Anaesthesia and Analgesia

View full text Add to dashboard Cite

Pharmacokinetics of the cytochrome P‐450 substrates phenytoin, theophylline, and diazepam in healthy Greyhound dogs

Cited by 11 publications

References 15 publications

Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus

Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus

Pharmacokinetics of a modified, compounded theophylline product in dogs

Pharmacokinetics of intravenous and oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs

Contact Info

Product

Resources

About