Pharmacokinetics of oestriol after repeated oral administration to dogs

The aim of the present study was to investigate the pharmacokinetics of oestriol in plasma in the dog after repeated oral administration of oestriol tablets, a preparation intended for the treatment of urinary incontinence in the bitch. The study was performed in six healthy, entire, adult female beagle dogs. The bitches were treated once daily with two tablets, containing 1 mg oestriol per tablet, for seven consecutive days (days 1-7). Blood samples were taken from the jugular vein before treatment, frequently on days 1, 3 and 7 of the treatment period and daily just before (C(trough)) and 1 h after dosing (C(t=1h)). During the washout period samples were taken at a 24 h interval up to four days post-treatment. Oestriol concentrations were determined in plasma by radioimmunoassay. Pharmacokinetic parameters, AUC, C(max) and t(max), were determined from the plasma concentration-time curves using non-compartmental methods. The between animal variation in C(max) and the AUC was high. Individual values of the C(max) varied from 206 pg/ml (day 1) to 1128 pg/ml (day 7) and the AUC(0-24h) from 789 pg x h/ml (day 1) to 5718 pg x h/ml (day 7). t(max) occurred within 1 h. The mean C(trough) value was slightly above the pre-treatment level ( 38+/-2 pg/ml vs. 18+/-5 pg/ml). Within 48 h after the last treatment the concentrations had returned to the pre-treatment values. C(max) and C(trough) did not increase during the treatment period, indicating that no accumulation occurred. A shoulder in the concentration-time curve around 8-12 h after treatment strongly suggested the existence of enterohepatic recirculation (EHR). The average relative contribution of the EHR to the AUC(0-24h) was estimated to be 22%, 38% and 44% on days 1, 3 and 7, respectively. These mean values were calculated from five animals per time point, because one dog failed to show EHR on days 1 and 3 and was therefore excluded from the calculations.     

Pharmacokinetics of pentoxifylline in dogs after oral and intravenous administration

OBJECTIVE: To evaluate the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl-metabolite, metabolite 1 (M1), in dogs after IV administration of a single dose and oral administration of multiple doses. ANIMALS: 7 sexually intact, female, mixed-breed dogs. PROCEDURE: A crossover study design was used so that each of the dogs received all treatments in random order. A drug-free period of 5 days was allowed between treatments. Treatments included IV administration of a single dose of PTX (15 mg/kg of body weight), oral administration of PTX with food at a dosage of 15 mg/kg (q 8 h) for 5 days, and oral administration of PTX without food at a dosage of 15 mg/kg (q 8 h) for 5 days. Blood samples were taken at 0.25, 0.5, 1, 1.5, 2, 2.5, and 3 hours after the first and last dose of PTX was administered PO, and at 5, 10, 20, 40, 80, and 160 minutes after PTX was administered IV. RESULTS: PTX was rapidly absorbed and eliminated after oral administration. Mean bioavailability after oral administration ranged from 15 to 32% among treatment groups and was not affected by the presence of food. Higher plasma PTX concentrations and apparent bioavailability were observed after oral administration of the first dose, compared with the last dose during the 5-day treatment regimens. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, oral administration of 15 mg of PTX/kg results in plasma concentrations similar to those produced by therapeutic doses in humans, and a three-times-a-day dosing regimen is the most appropriate.     

Pharmacokinetics of marbofloxacin in dogs after oral and parenteral administration

Six dogs were treated with a single intravenous (i.v.) dose (2 mg/kg) of marbofloxacin, followed by single oral (p.o.) doses of marbofloxacin at 1, 2 and 4 mg/kg, according to a three-way crossover design. The same experimental design was used for the subcutaneous (s.c.) route. In addition, a long-term trial involving eight dogs given oral doses of marbofloxacin at 2, 4 and 6 mg/kg/day for thirteen weeks was carried out. Plasma and urine samples were collected during the first two trials, plasma and skin samples were collected after the second of these trials. Plasma, urine and skin concentrations of marbofloxacin were determined by a reverse phase liquid chromatographic method. Mean pharmacokinetic parameters after i.v. administration were the following: t1/2β=12.4h; Cl _B= 0.10 L/h.kg; V _area= 1.9 L/kg. The oral bioavailability of marbofloxacin was close to 100% for the three doses. At 2 mg/kg, C _max of 1.4 μg/mL was reached at t _max of 2.5 h. Mean AUC and C _max values had a statistically significant linear relationship with the doses administered. About 40% of the administered dose was excreted in urine as unchanged parent drug. After s.c. administration, the calculated parameters were close to those obtained after oral administration, except t _max (about 1 h) which was shorter. The mean skin to plasma concentration ratio after the long-term trial was 1.6, suggesting good tissue penetration of marbofloxacin.     

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 carvedilol after intravenous and oral administration in conscious healthy dogs

OBJECTIVE: To determine the pharmacokinetics of carvedilol administered IV and orally and determine the dose of carvedilol required to maintain plasma concentrations associated with anticipated therapeutic efficacy when administered orally to dogs. ANIMALS: 8 healthy dogs. PROCEDURES: Blood samples were collected for 24 hours after single doses of carvedilol were administered IV (175 microg/kg) or PO (1.5 mg/kg) by use of a crossover nonrandomized design. Carvedilol concentrations were detected in plasma by use of high-performance liquid chromatography. Plasma drug concentration versus time curves were subjected to noncompartmental pharmacokinetic analysis. RESULTS: The median peak concentration (extrapolated) of carvedilol after IV administration was 476 ng/mL (range, 203 to 1,920 ng/mL), elimination half-life (t(1/2)) was 282 minutes (range, 19 to 1,021 minutes), and mean residence time (MRT) was 360 minutes (range, 19 to 819 minutes). Volume of distribution at steady state was 2.0 L/kg (range, 0.7 to 4.3 L/kg). After oral administration of carvedilol, the median peak concentration was 24 microg/mL (range, 9 to 173 microg/mL), time to maximum concentration was 90 minutes (range, 60 to 180 minutes), t(1/2) was 82 minutes (range, 64 to 138 minutes), and MRT was 182 minutes (range, 112 to 254 minutes). Median bioavailability after oral administration of carvedilol was 2.1% (range, 0.4% to 54%). CONCLUSIONS AND CLINICAL RELEVANCE: Although results suggested a 3-hour dosing interval on the basis of MRT, pharmacodynamic studies investigating the duration of beta-adrenoreceptor blockade provide a more accurate basis for determining the dosing interval of carvedilol.     

Pharmacokinetics of ketorolac after intravenous and oral single dose administration in dogs

The pharmacokinetics of ketorolac (Toradol), a human non-narcotic, nonsteroidal anti-inflammatory drug (NSAID) of the pyrrolo-pyrrole group, was studied in six mixed breed dogs of varying ages (1-5 years). The study was performed using a randomized crossover design, with each dog initially assigned to one of two groups (intravenous (i.v.) or oral (p.o.)). Each group of three dogs received either the injectable or oral formulation of ketorolac tromethamine at 0.5 mg/kg. Serial blood samples were collected before and over 96 h following treatment. Samples were analysed by reverse phase HPLC. Individual ketorolac plasma concentration-time curves were initially evaluated by computerized curve stripping techniques followed by nonlinear least squares regression. Following i.v. administration mean (+/- SD) pharmacokinetic parameters were: elimination half-life (t1/2 beta) = 4.55 h, plasma clearance (Clp) = 1.25 (1.13) mL/kg/min, and volume of distribution at steady state (Vss) = 0.33 (0.10) L/kg. Mean (+/- SD) p.o. pharmacokinetic values were: t1/2 beta = 4.07 h, time to reach maximum concentration (tmax) = 51.2 (40.6) min, and p.o. bioavailability (F) = 100.9 (46.7)%. These results suggest that the pharmacodisposition characteristics of a clinically effective 0.5 mg/kg i.v. or p.o. single dose of ketorolac tromethamine administered to dogs is fairly similar to that observed in humans.     

Pharmacokinetics in dogs after oral administration of two different forms of ascorbic acid

The authors evaluated the cell growth inhibition, reduction of tumourigenicity, and differentiation-inducing effects of sodium phenylacetate (NaPA) on a canine mammary tumour cell line. Treatment of the canine mammary tumour cell line (MCM-B2) with NaPA lead to the arrest of cell growth. Sodium phenylacetate induced changes in the cells to non-malignant characteristics, as indicated by a reduction of colony formation in semi-solid agar and a decrease in tumour formation in athymic mice. Moreover, NaPA induced morphological changes from a spindle-shaped to an epithelial-like appearance, and significant accumulation of lipid droplets in the cytoplasm. Immunohistochemically, these treated cells reacted clearly with the antibody for keratin/cytokeratin. Sodium phenylacetate treatment increased the expression of the milk-specific genes alpha-lactalbumin and beta-casein. The results of this study warrant an evaluation of NaPA in a clinical trial to establish its possible value as adjunctive treatment of malignant canine mammary tumours.     

Pharmacokinetics of cyclophosphamide after oral and intravenous administration to dogs with lymphoma

Background: Cyclophosphamide is an alkylating chemotherapeutic drug administered IV or PO. It is currently assumed that exposure to the active metabolite, 4‐hydroxycyclophosphamide (4‐OHCP), is the same with either route of administration.

Objectives:

To characterize the pharmacokinetics of cyclophosphamide and 4‐OHCP in dogs with lymphoma when administered PO or IV. Animals: Sixteen client‐owned dogs with substage A lymphoma were enrolled in the study. Eight dogs received cyclophosphamide IV and 8 received it PO. Methods: Prospective randomized clinical trial was performed. Blood was collected from each dog at specific time points after administration of cyclophosphamide. The serum was evaluated for the concentration of cyclophosphamide and 4‐OHCP with mass spectrometry and liquid chromatography. Results: Drug exposure to cyclophosphamide measured by area under the curve (AUC)_0–inf is significantly higher after intravenous administration (7.14 ± 3.77 μg/h/mL) compared with exposure after oral administration (P‐value < .05). No difference in drug exposure to 4‐OHCP was detected after IV (1.66 ± 0.36 μg/h/mL) or PO (1.42 ± 0.64 μg/h/mL) administered cyclophosphamide. Conclusions and Clinical Importance: Drug exposure to the active metabolite 4‐OHCP is equivalent after administration of cyclophosphamide either PO or IV.     

Pharmacokinetics of single-dose oral pregabalin administration in normal dogs

ObjectiveTo describe the pharmacokinetics of pregabalin in normal dogs after a single oral dose.Study designProspective experiment.AnimalsSix adult Labrador/Greyhound dogs (four females and two males) aged 2.6 (2.6–5.6) years old (median and range) weighing 33.4 (26.8–42.1) kg.MethodsAfter jugular vein catheterization, the dogs received a single oral dose of pregabalin (～4 mg kg^?1). Blood samples were collected at: 0 (before drug administration), 15 and 30 minutes and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 hours after drug administration. Plasma pregabalin concentration was measured by HPLC. Noncompartmental analysis was used to estimate pharmacokinetic variables.ResultsNo adverse effects were observed. The median (range) pharmacokinetic parameters were: Area under the curve from time 0 to 36 hours = 81.8 (56.5–92.1) μg hour mL^?1; absorption half-life = 0.38 (0.25–1.11) hours; elimination half-life = 6.90 (6.21–7.40) hours; time over 2.8 μg mL^?1 (the presumed minimal effective concentration) = 11.11 (6.97–14.47) hours; maximal plasma concentration (C_max) = 7.15 (4.6–7.9) μg mL^?1; time for C_max to occur = 1.5 (1.0–4.0) hours. Assuming an 8-hour dosing interval, predicted minimal, average, and maximal steady state plasma concentrations were 6.5 (4.8–8.1), 8.8 (7.3–10.9), and 13.0 (8.8–15.2) μg mL^?1. The corresponding values assuming a 12-hour interval were 3.8 (2.4–4.8), 6.8 (4.9–7.9), and 10.1 (6.6–11.6) μg mL^?1.Conclusions and clinical relevancePregabalin 4 mg kg^?1 PO produces plasma concentrations within the extrapolated therapeutic range from humans for sufficient time to suggest that a twice daily dosing regime would be adequate. Further study of the drug's safety and efficacy for the treatment of neuropathic pain and seizures in dogs is warranted.     

Pharmacokinetics of buprenorphine in a sodium carboxymethylcellulose gel after buccal transmucosal administration in dogs

Alternatives to intravenous administration of opioids are needed in veterinary medicine. Previous research suggests that opioids can be administered through the buccal mucosa in dogs. This study reports the pharmacokinetics of buprenorphine HCl (0.05 mg/kg) administered transmucosally in six dogs compared with those of buprenorphine HCl (0.015 mg/kg) administered intravenously. The results suggest that the pharmacokinetics of buprenorphine HCl administered intravenously or transmucosally are similar and that transmucosal administration may be considered as a noninvasive alternative to intravenous administration.     

Pharmacokinetics of methylphenidate after oral administration of immediate and sustained-release preparations in Beagle dogs

Methylphenidate (MPH) is a drug administered either as an immediate- or sustained-release preparation for the treatment of attention deficit hyperactivity disorder in humans. The aim of this study was to determine the pharmacokinetics of two different MPH formulations in the dog. Eight dogs were randomly assigned to two treatment groups using a two-part randomised, cross-over experimental design. Each subject received a single dose of 20 mg d,l-MPH as an immediate- (IR) or sustained-release (SR) tablet. Blood was collected at specific times, and the plasma concentrations of d,l-MPH were evaluated using high performance liquid chromatography.There were no adverse effects following the oral administration of d,l-MPH in either the IR or SR groups, apart from mild hyperkinesia which was observed in some of the IR group. The plasma concentration data of d,l-MPH were best described by a one-compartment model. There were significant differences in the maximum concentration (C_max), time to C_max (T_max), area under the curve (AUC) and clearance (Cl) between the two formulations. The relative bioavailability of the SR formulation was 30.58 ± 13.73% and, despite low drug plasma concentrations, the SR formulation resulted in uniform plasma concentrations of d,l-MPH. However, the dose rate of the SR formulation used in this study resulted in plasma concentrations that were below effective levels for clinical efficacy, so further studies are required to confirm the suitability of higher dose rates for clinical use.     

Pharmacokinetics of aditoprim in dogs after intravenous and oral administration: a preliminary study

The pharmacokinetics of aditoprim (2,4-diam-ino-5-[4-[dimethylamino]-3,5-dimethoxybenzyl] pyrimidine), a dihydrofolate reductase inhibitor, were studied in three eight to 17-month-old beagle dogs. The drug was alternately injected intravenously and administered orally as a tablet in two separate experiments. The doses ranged from 4–27 to 7–25 mg/kg bodyweight. The mean plasma clearance (CI) was 15-3 ml/min/kg and the mean volume of distribution (V_ss) 13-1 litres/kg. The mean plasma elimination half-life times after intravenous injection and oral administration were 11-6 and 9-6 hours, respectively. Aditoprim was readily (t_max= one to four hours) and completely absorbed from the intestinal tract (f = 89 per cent).     

Pharmacokinetics of cephalexin in dogs and cats after oral, subcutaneous and intramuscular administration

A three-way crossover study was carried out in 10 dogs and nine cats to establish the pharmacokinetic parameters of the semi-synthetic cephalosporin antibiotic, cephalexin sodium, when administered orally, subcutaneously or intramuscularly. Ten dogs received a subcutaneous or intramuscular injection of 10 mg/kg bodyweight cephalexin or an oral dose of three 50 mg cephalexin tablets; the peak serum concentrations achieved were 24.9, 31.9 and 18.6 micrograms/ml, respectively, and the times taken to reach these peak levels were 1.2, 0.9 and 1.8 hours. Nine cats received either a subcutaneous or intramuscular dose of 0.25 ml cephalexin suspension (approximately 20 mg/kg bodyweight) or an oral dose of one 50 mg tablet; the peak serum concentrations achieved were 54.0, 61.8 and 18.7 micrograms/ml for the subcutaneous, intramuscular and oral administrations respectively, with times to peak concentrations of 1.1, 0.7 and 2.6 hours.     

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.     

Pharmacokinetics of tilmicosin after oral administration in swine

OBJECTIVE: To determine the pharmacokinetics of tilmicosin after oral administration of a single dose of tilmicosin base in swine. ANIMALS: 10 healthy swine. PROCEDURE: Tilmicosin base was administered via stomach tube at a single dose of 20 mg/kg (n = 5) or 40 mg/kg (5). Blood samples were obtained from a jugular vein immediately before and at 10, 20, and 30 minutes and 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours after administration of tilmicosin. Tilmicosin concentrations in serum were quantified by use of a high-performance liquid chromatography procedure with UV light. Data for tilmicosin concentrations versus time were analyzed by use of compartmental and noncompartmental methods. RESULTS: Tilmicosin concentrations in serum decreased in a biexponential manner after oral administration. Mean +/- SD values for absorption half-lives were 1.49 +/- 0.23 hours and 1.64 +/- 0.40 hours, distribution half-lives were 2.96 +/- 0.58 hours and 3.20 +/- 0.76 hours, elimination half-lives were 25.26 +/- 8.25 and 20.69 +/- 5.07 hours, peak concentrations were 1.19 +/- 0.30 microg/mL and 2.03 +/- 0.28 microg/mL, and time to peak concentrations was 3.12 +/- 0.50 hours and 3.48 +/- 0.77 hours after oral administration of tilmicosin base at a single dose of 20 or 40 mg/kg, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: In swine, tilmicosin was rapidly absorbed and slowly eliminated after oral administration of a single dose of tilmicosin base powder.     

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.     

Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs

Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single‐dose, operator‐blinded, parallel‐dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24‐h period following dosing. Pimobendan and its active metabolite were quantified using an ultra‐high‐performance liquid chromatography–mass spectrometer (UHPLC‐MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (T_max) 1.1 h] and readily converted to the active metabolite (metabolite T_max 1.3 h). The elimination half‐life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2–4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs.     

Pharmacokinetics of buprenorphine following intravenous and oral transmucosal administration in dogs

Pharmacokinetic analysis of buprenorphine administered to six healthy dogs via the oral transmucosal (OTM) route at doses of 20 and 120 microg/kg was conducted using liquid chromatography-electrospray ionization-tandem mass spectroscopy (LC-ESI-MS/MS). Bioavailability was 38% plus or minus 12% for the 20 microg/kg dose and 47%+/-16% for the 120 microg/kg dose. Maximum plasma concentrations were similar for buprenorphine doses of 20 microg/kg IV and 120 microg/kg OTM. Sedation and salivation were common side effects, but no bradycardia, apnea, or cardiorespiratory depressive effects were seen. When the two OTM dosing rates were normalized to dose, LC-ESI-MS/MS analysis of buprenorphine and its metabolites detected no significant difference (P>.05), indicating dose proportionality. The results of this study suggest that OTM buprenorphine may be an alternative for pain management in dogs.     

Pharmacokinetics of clomipramine in dogs following single-dose and repeated-dose oral administration

OBJECTIVE: To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs following single-dose and repeated-dose oral administration at various dosages. ANIMALS: 9 male and 9 female Beagles. PROCEDURES: Clomipramine was administered orally at a dose of 1, 2, or 4 mg/kg to 3 male and 3 female dogs, first as a single dose and then, after an interval of 14 days, twice daily for 10 days. Plasma clomipramine and desmethylclomipramine concentrations were measured by use of a gas chromatography with mass-selection method. RESULTS: Dose-related accumulation was detected following repeated-dose administration. Accumulation ratios after administration of clomipramine at dosages of 1, 2, and 4 mg/kg twice daily were 1.4, 1.6, and 3.8, respectively, for clomipramine and 2.1, 3.7, and 7.6, respectively, for desmethylclomipramine. Terminal half-life increased slightly (1.6-fold for clomipramine and 1.2-fold for desmethylclomipramine) with repeated-dose administration but remained short in all groups (< or = 4 hours). Steady state was reached within 4 days in all animals. Ratios of the areas under the concentration versus time curves from time 0 to 12 hours for clomipramine and desmethylclomipramine were 3.9, 3.1, and 1.5 after repeated administration at dosages of 1, 2, and 4 mg/kg every 12 hours, respectively. Areas under the concentration versus time curve, mean residence times, and terminal half-lives were not significantly different between male and female dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Repeated administration of clomipramine results in higher concentrations of clomipramine than desmethylclomipramine in dogs.