Clinical pharmacokinetics of a dexmedetomidine–methadone combination in dogs undergoing routine anaesthesia after buccal or intramuscular administration

This study aimed to define the pharmacokinetic profiles of dexmedetomidine and methadone administered simultaneously in dogs by either an oral transmucosal route or intramuscular route and to determine the bioavailability of the oral transmucosal administration relative to the intramuscular one of both drugs, so as the applicability of this administration route in dogs. Twelve client‐owned dogs, scheduled for diagnostic procedures, were treated with a combination of dexmedetomidine hydrochloride (10 μg/kg) and methadone hydrochloride (0.4 mg/kg) through an oral transmucosal route or intramuscularly. Oral transmucosal administration caused ptyalism in most subjects, and intramuscular administration caused transient peripheral vasoconstriction. The results showed reduced and delayed absorption of both dexmedetomidine and methadone when administered through an oral transmucosal route, with median (range) C_max values of 0.82 (0.42–1.49) ng/ml and 13.22 (2.80–52.30) ng/ml, respectively. The relative bioavailability was low: 16.34% (dexmedetomidine) and 15.5% (methadone). Intramuscular administration resulted in a more efficient absorption profile, with AUC and C_max values for both drugs approximately 10 times higher. Dexmedetomidine and methadone administered simultaneously by an oral transmucosal route using injectable formulations were not well absorbed through the oral mucosa. Nevertheless, additional studies on these drugs combination using alternative administration routes are recommended.     

Pharmacokinetics of levofloxacin after single intravenous,oral and subcutaneous administration to dogs

The pharmacokinetic properties of the fluoroquinolone levofloxacin (LFX) were investigated in six dogs after single intravenous, oral and subcutaneous administration at a dose of 2.5, 5 and 5 mg/kg, respectively. After intravenous administration, distribution was rapid (T_½dist 0.127 ± 0.055 hr) and wide as reflected by the volume of distribution of 1.20 ± 0.13 L/kg. Drug elimination was relatively slow with a total body clearance of 0.11 ± 0.03 L kg^?1 hr^?1 and a T_½ for this process of 7.85 ± 2.30 hr. After oral and subcutaneous administration, absorption half‐life and T_max were 0.35 and 0.80 hr and 1.82 and 2.82 hr, respectively. The bioavailability was significantly higher (p ? 0.05) after subcutaneous than oral administration (79.90 vs. 60.94%). No statistically significant differences were observed between other pharmacokinetic parameters. Considering the AUC_24 hr/MIC and C_max/MIC ratios obtained, it can be concluded that LFX administered intravenously (2.5 mg/kg), subcutaneously (5 mg/kg) or orally (5 mg/kg) is efficacious against Gram‐negative bacteria with MIC values of 0.1 μg/ml. For Gram‐positive bacteria with MIC values of 0.5 μg/kg, only SC and PO administration at a dosage of 5 mg/kg showed to be efficacious. MIC‐based PK/PD analysis by Monte Carlo simulation indicates that the proposed dose regimens of LFX, 5 and 7.5 mg/kg/24 hr by SC route and 10 mg/kg/24 hr by oral route, in dogs may be adequate to recommend as an empirical therapy against S. aureus strains with MIC ≤ 0.5 μg/ml and E. coli strains with MIC values ≤0.125 μg/ml.     

The effects of ketoconazole and cimetidine on the pharmacokinetics of oral tramadol in greyhound dogs

Tramadol is administered to dogs for analgesia but has variability in its extent of absorption, which may hinder its efficacy. Additionally, the active opioid metabolite (M1) occurs in low concentrations. The purpose of this study was to determine if administration of oral tramadol with suspected metabolism inhibitors (ketoconazole, cimetidine) would lead to improved bioavailability of tramadol and M1. Six healthy Greyhounds were included. They were administered tramadol orally and intravenously, M1 intravenously, oral tramadol with oral ketoconazole and oral tramadol with oral cimetidine. Oral tramadol bioavailability was low (2.6%). Ketoconazole and cimetidine significantly increased tramadol bioavailability to 18.2% and 20.3%, respectively. The mean maximum plasma concentration of tramadol alone was 22.9 ng/ml, and increased to 109.9 and 143.2 ng/ml with ketoconazole and cimetidine, respectively. However, measured tramadol plasma concentrations were below the minimum concentration considered effective in humans (228 μg/ml). In all treatment groups, measured M1 concentrations (<7 μg/ml) were below concentrations associated with efficacy in humans. To conclude, tramadol and M1 concentrations were low and variable in dogs after oral dosing of tramadol, even in combination with cimetidine or ketoconazole, but effective concentrations in dogs have not been defined.     

The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs

Methadone is an opioid, which has a high oral bioavailability (>70%) and a long elimination half-life (>20 h) in human beings. The purpose of this study was to evaluate the effects of ketoconazole [a CYP3A and p-glycoprotein (p-gp) inhibitor] and omeprazole (an H+,K(+)-ATPase proton-pump inhibitor) on oral methadone bioavailability in dogs. Six healthy dogs were used in a crossover design. Methadone was administered i.v. (1 mg/kg), orally (2 mg/kg), again orally following oral ketoconazole (10 mg/kg q12 h for two doses), and following omeprazole (1 mg/kg p.o. q12 h for five doses). Plasma concentrations of methadone were analyzed by high-pressure liquid chromatography or fluorescence polarization immunoassay. The mean +/- SD for the elimination half-life, volume of distribution, and clearance were 1.75 +/- 0.25 h, 3.46 +/- 1.09 L/kg, and 25.14 +/- 9.79 mL/min.kg, respectively following i.v. administration. Methadone was not detected in any sample following oral administration alone or following oral administration with omeprazole. Following administration with ketoconazole, detectable concentrations of methadone were present in one dog with a 29% bioavailability. MDR-1 genotyping, encoding p-gp, was normal in all dogs. In contrast to its pharmacokinetics humans, methadone has a short elimination half-life, rapid clearance, and low oral bioavailability in dogs and the extent of absorption is not affected by inhibition of CYP3A, p-gp, and gastric acid secretion.     

Effect of oral administration of unfractionated heparin (UFH) on coagulation parameters in plasma and levels of urine and fecal heparin in dogs

The effects of heparin administration, by the oral route, were evaluated in dogs. In single and multiple dose studies (single 7.5 mg/kg, multiple 3 × 7.5 mg/kg per 48 h), plasma, urine, and fecal samples were collected at various times up to 120 h after oral administration of unfractionated heparin. Changes in plasma and urine anti-Xa activity, plasma and urine anti-IIa activity, plasma activated partial thromboplastin time (APTT) and antithrombin (ATIII), and chemical heparin in urine and feces were examined with time. There was support for heparin absorption, with significant differences in APTT, heparin in plasma as determined by anti-Xa activity (Heptest) in the single dose study and plasma anti-Xa activity, anti-IIa activity and ATIII; and chemical heparin in urine in the multiple dose study. No clinical evidence of bleeding was detected in any dog during the studies. Oral heparin therapy may be applicable for thromboembolic disease in animals. Further studies are warranted to determine the effects of oral heparin at the endothelial level in the dog.     

The pharmacokinetics of cytarabine in dogs when administered via subcutaneous and continuous intravenous infusion routes

This crossover study compared the pharmacokinetics of cytarabine in six healthy dogs following intravenous constant rate infusion (CRI) and subcutaneous (SC) administrations, as these are two routes of administration commonly employed in the treatment of meningoencephalitis of unknown etiology. Each dog received a SC cytarabine injection of 50 mg/m² or an 8 h CRI of 25 mg/m² per hour, with a 7‐day washout before receiving the alternative treatment. Blood samples were collected for 16 h after CRI initiation and for 8 h after SC injection. Plasma concentrations were measured by high‐pressure liquid chromatography (HPLC). Pharmacokinetic parameters were estimated using the best‐fit compartmental analysis for both CRI and SC routes. Terminal half‐life (T_½) of cytarabine was 1.35 ± 0.3 and 1.15 ± 0.13 h after SC administration and CRI, respectively. Mean peak concentration (C_max) was 2.88 and 2.80 μg/mL for SC and CRI administration, respectively. Volume of distribution was 0.66 ± 0.07 l/kg. The 8‐h CRI produced steady‐state plasma concentrations as determined by consecutive measurement that did not decline until the end of the infusion. The SC administration did not achieve steady‐state concentrations because cytarabine administered by this route was rapidly absorbed and eliminated quickly. The steady state achieved with the cytarabine CRI may produce a more prolonged exposure of cytarabine at cytotoxic levels in plasma compared to the concentrations after SC administration.     

Pharmacokinetics of low-dose methotrexate in horses

This study aimed to investigate both the pharmacokinetic behavior and tolerance of methotrexate (MTX) in horses to design a specific dosing regimen as a new immunomodulatory drug for long-term treatment. To determine the primary plasma pharmacokinetic variables after single intravenous, subcutaneous or oral administration, six horses were administered 0.3 mg/kg MTX in a crossover design study. After a 10-week washout, MTX was administered subcutaneously to three of the six previously treated horses at a dose of 0.3 mg/kg once per week for 3 months. In both studies, MTX and metabolite concentrations were measured using LC-MS/MS. The absolute bioavailability of MTX was 73% following subcutaneous administration but less than 1% following oral administration. The plasma clearance was 1.54 ml min⁻¹ kg⁻¹ (extraction ratio = 2%). After 24 hr, plasma concentrations were below the LOQ. No adverse effects were noted except for a moderate reversible elevation in liver enzymes (GLDH). With regards to the main metabolites of MTX, very low concentrations of 7-hydroxy-MTX were found, whereas polyglutamated forms (mainly short chains) were found in red blood cells. A subcutaneous dose of 0.2 mg kg⁻¹ week⁻¹ may be safe and relevant in horses, although this has yet to be clinically confirmed.     

Pharmacokinetic analysis of mosapride following intravenous and oral administration in beagle dogs

The aim of this study was to investigate the pharmacokinetic properties of mosapride after intravenous and oral administration to beagle dogs. To obtain the advanced pharmacokinetic parameters of mosapride, both noncompartmental analysis and pharmacokinetic modeling were performed. Twenty beagle dogs were randomly sorted into intravenous (1 mg single administration of mosapride) and oral (5 mg once a day administration of mosapride) groups. Blood samples were collected according to the reported schedule for pharmacokinetics. The plasma concentration of mosapride was analyzed using liquid chromatography–tandem mass spectrometry. According to the pharmacokinetic analysis, the absorption rate of mosapride was 3.14 ± 1.14 hr⁻¹ and oral bioavailability of mosapride was approximately 1%. The one-compartment model well described the pharmacokinetics of mosapride after both intravenous and oral administration to dogs. These findings will help facilitate the determination of the optimal dose regimen of mosapride for dogs with gastrointestinal disorder.     

Bioavailability of levamisole after intramuscular and oral administration in sheep

AIMS: To determine the bioavailability of levamisole in sheep. METHODS: Levamisole was administered to three groups of six Merino sheep orally and intramuscularly at three dose levels of 5, 7.5 and 10 mg/kg. There was a washout period of 1 week between treatments. Blood samples were collected by jugular venepuncture and plasma was separated immediately by centrifugation and stored at 20 degrees C until analysed. The levamisole concentration in plasma was determined by high performance liquid chromatography with a U.V. detection method. Individual plasma levamisole concentration-time data were analysed using the compartmental method. RESULTS: The values obtained for k(a), C(max), t(max) and F show a moderate rate and extent of absorption after oral administration of levamisole while, after intramuscular administration, these values demonstrate a high rate and extent of absorption of levamisole. The intramuscular bioavailability was higher than the oral bioavailability (rate of absorption three-fold faster, extent of absorption 25-33% higher and C(max) two-fold higher). The Friedman test involving dose and route of administration showed that the route of administration affects k(a), C(max), t(max) and F; significant differences were found in these parameters. CLINICAL RELEVANCE: On the basis of these data, the recommended routes for the administration of levamisole in sheep are oral for gastro-intestinal nematodiasis and intramuscular for extragastric nematodiasis.     

Effect of sucralfate on oral minocycline absorption in healthy dogs

Sucralfate and minocycline may be administered concurrently to dogs. The relative bioavailability of tetracyclines may be reduced if administered with sucralfate, but studies confirming these interactions in dogs are not available. This study evaluated the pharmacokinetics of oral minocycline in dogs (M), determined the effects of concurrent administration of sucralfate and minocycline (MS) on minocycline pharmacokinetics, determined the effects of delaying sucralfate administration by 2 h (MS+2) on minocycline pharmacokinetics, and established dosing recommendations based on pharmacodynamic indices. Oral minocycline (300 mg) and sucralfate suspension (1 g) were administered to five greyhounds in a randomized crossover design. Minocycline plasma concentrations were evaluated using liquid chromatography with mass spectrometry. The maximum plasma concentration (C_MAX) and area under the curve (AUC) of minocycline were 1.15 μg/mL and 8.0 h* μg/mL, respectively. The C_MAX and AUC were significantly lower (P < 0.05) in the MS group (C_MAX = 0.33 μg/mL, AUC 3.0 h*μg/mL) compared with M or MS+2 (C_MAX = 0.97 μg/mL, AUC 10.3 h*μg/mL). Delaying sucralfate by 2 h did not decrease oral minocycline absorption, but concurrent administration significantly decreased minocycline absorption. A dose of 7.5 mg/kg p.o. q12 h achieves the pharmacodynamic index for a bacterial minimum inhibitory concentration (MIC) of 0.25 μg/mL (AUC:MIC≥33.9).     

Pharmacokinetics of a modified,compounded theophylline product in dogs

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.     

Pharmacokinetics, pharmacodynamics, and analgesic effects of morphine after rectal, intramuscular, and intravenous administration in dogs

OBJECTIVE: To compare systemic bioavailability and duration for therapeutic plasma concentrations and cardiovascular, respiratory, and analgesic effects of morphine administered per rectum, compared with IV and IM administration in dogs. ANIMALS: 6 healthy Beagles. PROCEDURE: In a randomized study, each dog received the following: morphine IV (0.5 mg/kg of body weight), morphine per rectum (1, 2, and 5 mg/kg as a suppository and 2 mg/kg as a solution), and a control treatment. Intramuscular administration of morphine (1 mg/kg) was evaluated separately. Heart and respiratory rates, systolic, diastolic, and mean blood pressures, adverse effects, and plasma morphine concentrations were measured. Analgesia was defined as an increase in response threshold, compared with baseline values, to applications of noxious mechanical (pressure) and thermal (heat) stimuli. Data were evaluated, using Friedman repeated-measures ANOVA on ranks and Student-Newman-Keuls post-hoc t-tests. RESULTS: Significant differences were not found in cardiovascular, respiratory, or analgesia values between control and morphine groups. Overall systemic bioavailability of morphine administered per rectum was 19.6%. Plasma morphine concentration after administration of the highest dose (5 mg/kg) as a suppository was significantly higher than concentrations 60 and 360 minutes after IV and IM administration, respectively. A single route of administration did not consistently fulfill our criteria for providing analgesia. CONCLUSIONS AND CLINICAL RELEVANCE: Rectal administration of morphine did not increase bioavailability above that reported for oral administration of morphine in dogs. Low bioavailability and plasma concentrations limit the clinical usefulness of morphine administered per rectum in dogs.     

The pharmacokinetics of oclacitinib maleate,a Janus kinase inhibitor,in the dog

The pharmacokinetics of oclacitinib maleate was evaluated in four separate studies. The absolute bioavailability study used a crossover design with 10 dogs. The effect of food on bioavailability was investigated in a crossover study with 18 dogs. The breed effect on pharmacokinetics was assessed in a crossover study in beagles and mongrels dogs. Dose proportionality and multiple dose pharmacokinetics were evaluated in a parallel design study with eight dogs per group. In all four studies, serial blood samples for plasma were collected. Oclacitinib maleate was rapidly and well absorbed following oral administration, with a time to peak plasma concentration of <1 h and an absolute bioavailability of 89%. The prandial state of dogs did not significantly affect the rate or extent of absorption of oclacitinib maleate when dosed orally, as demonstrated by the lack of significant differences in pharmacokinetic parameters between the oral fasted and oral fed treatment groups. The pharmacokinetics of oclacitinib in laboratory populations of beagles and mixed breed dogs also appeared similar. Following oral administration, the exposure of oclacitinib maleate increased dose proportionally from 0.6 to 3.0 mg/kg. Additionally, across the pharmacokinetic studies, there were no apparent differences in oclacitinib pharmacokinetics attributable to sex.     

Pharmacokinetics of oral amantadine in greyhound dogs

This study reports the pharmacokinetics of amantadine in greyhound dogs after oral administration. Five healthy greyhound dogs were used. A single oral dose of 100 mg amantadine hydrochloride (mean dose 2.8 mg/kg as amantadine hydrochloride) was administered to nonfasted subjects. Blood samples were collected at predetermined time points from 0 to 24 h after administration, and plasma concentrations of amantadine were measured by liquid chromatography with triple quadrupole mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Amantadine was well tolerated in all dogs with no adverse effects observed. The mean (range) amantadine C_MAX was 275 ng/mL (225–351 ng/mL) at 2.6 h (1–4 h) with a terminal half‐life of 4.96 h (4.11–6.59 h). The results of this study can be used to design dosages to assess multidose pharmacokinetics and dosages designed to achieve targeted concentrations in order to assess the clinical effects of amantadine in a variety of conditions including chronic pain. Further studies should also assess the pharmacokinetics of amantadine in other dog breeds or using population pharmacokinetics studies including multiple dog breeds to assess potential breed‐specific differences in the pharmacokinetics of amantadine in dogs.     

Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets

Long-term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post-treatment ( t _max = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half-life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed ( t _max = 2.25 h) and decreased the rate and extent of absorption ( AUC ) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs.     

Pharmacokinetics of levamisole in the red‐eared slider turtles (Trachemys scripta elegans)

The pharmacokinetics and bioavailability of levamisole were determined in red‐eared slider turtles after single intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration. Nine turtles received levamisole (10 mg/kg) by each route in a three‐way crossover design with a washout period of 30 days. Blood samples were collected at time 0 (pretreatment), and at 0.25, 0.5, 1, 1.5, 3, 6, 9, 12, 18, 24, 36, and 48 hr after drug administration. Plasma levamisole concentrations were determined by a high‐performance liquid chromatography assay. Data were analyzed by noncompartmental methods. The mean elimination half‐life was 5.00, 7.88, and 9.43 hr for IV, IM, and SC routes, respectively. The total clearance and volume of distribution at steady state for the IV route were 0.14 L hr^?1 kg^?1 and 0.81 L/kg, respectively. For the IM and SC routes, the peak plasma concentration was 9.63 and 10.51 μg/ml, respectively, with 0.5 hr of T_max. The bioavailability was 93.03 and 115.25% for the IM and SC routes, respectively. The IM and SC route of levamisole, which showed the high bioavailability and long t_1/2?z, can be recommended as an effective way for treating nematodes in turtles.     

Pharmacokinetics of acetaminophen after intravenous and oral administration in fasted and fed Labrador Retriever dogs

Acetaminophen (paracetamol) is used in dogs to manage fever and mild pain. The aim of this study was to assess the pharmacokinetics of acetaminophen in both fed and fasted Labrador Retrievers after a single intravenous and oral administration (20 mg/kg). Six healthy dogs underwent three treatments in a randomized block study (a, n = 2; b, n = 2; c, n = 2). In phase one, group a received acetaminophen intravenously, group b and c orally after being fasted and fed, respectively. In phase two and three, groups were swapped, and the experiment was repeated. At the end of the trial, each dog received the same treatment. Acetaminophen plasma concentrations were detected using a validated HPLC‐UV method. The pharmacokinetic analysis was performed using a noncompartmental model. Clearance, volume at steady state and half‐life of acetaminophen in Labrador Retrievers were 0.42 L/kg hr, 0.87 L/kg and 1.35 hr, respectively. No significant statistical differences were found between fasted and fed dogs regarding maximum plasma concentration, time at maximum concentration and bioavailability as measured by the AUC. Feeding does not significantly affect the acetaminophen oral pharmacokinetics.     

Renal perfusion parameters measured by contrast‐enhanced ultrasound in healthy dogs demonstrate a wide range of variability in the long‐term

Contrast‐enhanced ultrasound may be helpful for detecting early renal microvascular damage and dysfunction in dogs. However, before this noninvasive imaging method can be tested as an early‐stage screening tool in clinical patients, an improved understanding of long‐term variation in healthy animals is needed. In this prospective, secondary, longitudinal, serial measurements study, variability of contrast‐enhanced ultrasound renal perfusion parameters was described for eight healthy dogs, using seven time points and a period of 83 weeks. Dogs were sedated with butorphanol (0.4 mg/kg), and contrast‐enhanced ultrasound of each kidney was performed after an intravenous bolus injection of a microbubble contrast agent (0.04 mL/kg). Time‐intensity curves were created from regions‐of‐interest drawn in the renal cortex and medulla. Intensity‐related parameters representing blood volume and time‐related parameters representing blood velocity were determined. A random‐effects model using restricted maximum likelihood was used to estimate variance components. Within‐dog coefficient of variation was defined as the ratio of the standard deviation over the mean. Time‐related parameters such as time‐to‐peak, rise and fall time had lowest within‐dog variability. Intensity‐related parameters such as peak enhancement, wash‐in and wash‐out area under the curve, total area under the curve, and wash‐in and washout rates had high within‐dog variability (coefficient of variation > 45%). Authors therefore recommend the use of time‐related parameters for future studies of renal perfusion. Within‐dog variability for bilateral kidney measurements was extremely low, therefore contrast‐enhanced ultrasound may be particularly useful for detecting unilateral changes in renal perfusion. Future studies are needed to compare contrast‐enhanced ultrasound findings in healthy dogs versus dogs with renal disease.     

Evaluation of the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in fed and fasted Greyhound dogs

This study reports the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs. Five healthy Greyhound dogs were enrolled in a randomized crossover design. A single oral dose of amitriptyline hydrochloride (actual mean dose 8.1 per kg) was administered to fasted or fed dogs. Blood samples were collected at predetermined times from 0 to 24 h after administration, and plasma drug concentrations were measured by liquid chromatography with mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Two dogs in the fasted group vomited following amitriptyline administration and were excluded from analysis. The range of amitriptyline C_MAX for the remaining fasted dogs (n = 3) was 22.8–64.5 ng/mL compared to 30.6–127 ng/mL for the fed dogs (n = 5). The range of the amitriptyline AUC_INF for the three fasted dogs was 167–720 h·ng/mL compared to 287–1146 h·ng/mL for fed dogs. The relative bioavailability of amitriptyline in fasted dogs compared to fed dogs was 69–91% (n = 3). The exposure of the active metabolite nortriptyline was correlated to amitriptyline exposure (R² = 0.84). Due to pharmacokinetic variability and the small number of dogs completing this study, further studies are needed assessing the impact of feeding on oral amitriptyline pharmacokinetics. Amitriptyline may be more likely to cause vomiting in fasted dogs.     

Long-lasting enhancement of CYP activity after discontinuation of repeated administration of phenobarbital in dogs

We investigated how long in vivo hepatic cytochrome P450 (CYP) activity is enhanced even after discontinuation of repeated oral administration of phenobarbital (PB) in dogs using antipyrine clearance, which reflects hepatic CYP activity. A single antipyrine (5 mg/kg) was administered intravenously before and 34 days after the repeated oral administration of PB (5 mg/kg, bid) and 2, 4, 6, and 8 weeks after the discontinuation of PB in 5 dogs. Antipyrine clearance was increased by the repeated administration of PB, and remained increased 2 and 4, but not 6 and 8 weeks after the discontinuation of PB. The result suggests that hepatic CYP activity was enhanced by the repeated administration of PB, and this enhancement may last for at least 4 weeks even after its discontinuation.