Pharmacokinetics of clomipramine and desmethylclomipramine after single-dose intravenous and oral administrations in cats

A cross-over study was performed in six adult spayed cats to determine the pharmacokinetics of clomipramine and its metabolite, desmethylclomipramine (DCMP) after intravenous (0.25 mg/kg) and oral (0.5 mg/kg) single-dose administrations. Plasma clomipramine and DCMP were measured by high-performance liquid chromatography at regular intervals for up to 30 h. Intravenous clomipramine best fit a two-compartmental model yielding an elimination rate constant of 0.037-0.09 h(-1) from which a mean half-life of 12.3 h was calculated. Mean clomipramine AUC(0--infinity) (ngxh/mL), clearance (L/hxkg), V(ss) (L/kg) and MRT (h) values were 652.5, 0.393, 5.0, and 13.5, respectively. Compartmental modeling for clomipramine, after oral administration, and DCMP after both administrations, produced wide parameter estimates and plots of residuals indicated poor goodness of fit. Noncompartmental analysis yielded mean AUC(0--30 h) (ngxh/mL), C(max) (ng/mL) and T(max) (h) of 948.3, 87.5 and 6.2 for clomipramine, and 613.8, 34.8, and 12.8 for DCMP respectively after oral administration. Clomipramine bioavailability was 90%. The present study showed marked pharmacokinetic variability for clomipramine and DCMP through biphasic absorption and potential genetic variability in clomipramine metabolism. It was concluded that population pharmacokinetics would allow better characterization of clomipramine variability that may explain the variability in clinical response noted in cats.     

Population pharmacokinetics of marbofloxacin in horses: preliminary analysis

Population pharmacokinetic of marbofloxacin was investigated on 21 healthy and 16 diseased horses to assess interindividual variability of drug exposure. Demographic, physiologic and disease covariables were tested using mixed effects models. As a preliminary analysis, this study has demonstrated that none of the tested covariables were significant in regression models for compartmental volumes or clearance of distribution, but the clinical status of the horse (healthy/diseased) was a significant covariable (P < 0.01) for systemic clearance. Clearance had a lower mean and a higher variance for diseased horses than healthy horses, with respectively a mean of 0.209 and 0.284 L/h/kg and a coefficient of variation of 52 and 15%. Consequently, variability of AUC was greater in diseased horses. Considering an AUC/MIC ratio below 60 h as a prediction of poor efficacy, a dosage regimen of 2 mg/kg intravenous was deemed to be inadequate for 19% of diseased horses if the MIC of the bacteria was 0.1 microg/mL. However 93% of diseased horses could achieve a ratio above 125 h, predicting a very good efficacy, for the MIC(90) of Enterobacteriacae (0.027 microg/mL).     

A Pharmacokinetic Comparison of Meloxicam and Ketoprofen following Oral Administration to Healthy Dogs

Ketoprofen (KTP) and meloxicam (MLX) are non-steroidal anti-inflamatory drugs used extensively in veterinary medicine. The pharmacokinetics of these drugs were studied in eight dogs following a single oral dose of 1 mg/kg of KTP as a racemate or 0.2 mg/kg of MLX. The concentrations of the drugs in plasma were determined by high-performance liquid chromatography (HPLC). There were differences between the disposition curves of the KTP enantiomers, confirming that the pharmacokinetics of KTP is enantioselective. (S)-(+)-KTP was the predominant enantiomer; the S:R ratio in the plasma increased from 2.58 +/- 0.38 at 15 min to 5.72 +/- 2.35 at 1 h. The area under the concentration time curve (AUC) of (S)-(+)-KTP was approximately 6 times greater than that of (R)-(-)-KTP. The mean (+/- SD) pharmacokinetic parameters for (S)-(+)-KTP were characterized as Tmax = 0.76 +/- 0.19 h, Cmax = 2.02 +/- 0.41 microg/ml, t1/2el = 1.65 +/- 0.48 h, AUC = 6.06 +/- 1.16 microg.h/ml, Vd/F = 0.39 +/- 0.07 L/kg, Cl/F = 170 +/- 39 ml/(kg.h). The mean (+/- SD) pharmacokinetic parameters of MLX were Tmax = 8.5 +/- 1.91 h, Cmax = 0.82 +/- 0.29 microg/ml, t1/2lambda(z) = 12.13 +/- 2.15 h, AUCinf = 15.41 +/- 1.24 microg.h/ml, Vd/F = 0.23 +/- 0.03 L/ kg, and Cl/F = 10 +/- 1.4 ml/(kg.h). Our results indicate significant pharmacokinetic differences between MLX and KTP after therapeutic doses.     

Pharmacokinetics of ivermectin in cats receiving a single subcutaneous dose

Ivermectin is effective against ecto- and endoparasites. It is included in a plan of the Filariasis Division, Thailand for filariasis control and prevention by interrupting transmission of Brugia malayi-microfilariae from cat reservoirs to humans via mosquitoes. The pharmacokinetics of ivermectin in eight healthy cats receiving a single subcutaneous dose of 0.2mg/kg was investigated. Jugular blood samples were collected periodically for up to 30days after dosing. The serum ivermectin concentrations were measured by high performance liquid chromatography with fluorescence detection. The pharmacokinetic parameters (mean+/-S.D.) derived from one-compartment model analysis were as follows: T(max) 1.22+/-0.49day, C(max) 16.75+/-4.04ng/mL, k(ab) 2.62+/-1.86day(-1), t(1/2)(ab) 0.27+/-0.25day, k(el) 0.27+/-0.14day(-1), t(1/2)(el) 2.53+/-2.24day, V(d)/F 9.81+/-5.41L/kg, Cl/F 2.21+/-0.69L/kg/day and AUC(0-->infinity) 98.31+/-30.52ngday/mL. In conclusion, the pharmacokinetics of ivermectin in cats receiving a single dose of 0.2mg/kg by subcutaneous injection revealed a rapid absorption, high distribution, slow elimination and high possibility for the elimination of B. malayi-microfilariae from currently endemic regions.     

Pharmacokinetics of selamectin following intravenous,oral and topical administration in cats and dogs

The pharmacokinetics of selamectin were evaluated in cats and dogs, following intravenous (0.05, 0.1 and 0.2 mg/kg), topical (24 mg/kg) and oral (24 mg/kg) administration. Following selamectin administration, serial blood samples were collected and plasma concentrations were determined by high performance liquid chromatography (HPLC). After intravenous administration of selamectin to cats and dogs, the mean maximum plasma concentrations and area under the concentration-time curve (AUC) were linearly related to the dose, and mean systemic clearance (Clb) and steady-state volume of distribution (Vd(ss)) were independent of dose. Plasma concentrations after intravenous administration declined polyexponentially in cats and biphasically in dogs, with mean terminal phase half-lives (t(1/2)) of approximately 69 h in cats and 14 h in dogs. In cats, overall Clb was 0.470 +/- 0.039 mL/min/kg (+/-SD) and overall Vd(ss) was 2.19 +/- 0.05 L/kg, compared with values of 1.18 +/- 0.31 mL/min/kg and 1.24 +/- 0.26 L/kg, respectively, in dogs. After topical administration, the mean C(max) in cats was 5513 +/- 2173 ng/mL reached at a time (T(max)) of 15 +/- 12 h postadministration; in dogs, C(max) was 86.5 +/- 34.0 ng/mL at T(max) of 72 +/- 48 h. Bioavailability was 74% in cats and 4.4% in dogs. Following oral administration to cats, mean C(max) was 11,929 +/- 5922 ng/mL at T(max) of 7 +/- 6 h and bioavailability was 109%. In dogs, mean C(max) was 7630 +/- 3140 ng/mL at T(max) of 8 +/- 5 h and bioavailability was 62%. There were no selamectin-related adverse effects and no sex differences in pharmacokinetic parameters. Linearity was established in cats and dogs for plasma concentrations up to 874 and 636 ng/mL, respectively. Pharmacokinetic evaluations for selamectin following intravenous administration indicated a slower elimination from the central compartment in cats than in dogs. This was reflected in slower clearance and longer t(1/2) in cats, probably as a result of species-related differences in metabolism and excretion. Inter-species differences in pharmacokinetic profiles were also observed following topical administration where differences in transdermal flux rates may have contributed to the overall differences in systemic bioavailability.     

Assessment of the influence of surgical technique on postoperative pain and wound tenderness in cats following ovariohysterectomy

Elective ovariohysterectomy was performed on 66 cats. Surgical approach was flank (group F) or midline (group M) allocated by block randomisation. Pre-anaesthetic medication was acepromazine (0.1 mg/kg) via intramuscular injection. Anaesthesia was induced with intravenous thiopentone, and maintained with halothane in 100% oxygen. Carprofen (4 mg/kg) was administered by the subcutaneous route immediately after induction of anaesthesia. Postoperative pain and wound tenderness were assessed at 1, 3, 6, 9, 11-12 and 20-24h after the end of surgery, and the assessment outcome marked on visual analogue scales (VAS). Intervention analgesia (if pain VAS was >40 mm) was pethidine 4 mg/kg via intramuscular injection. Area under the curve (AUC) for VAS for pain and VAS for wound tenderness for each cat were calculated. AUC for wound tenderness was significantly greater for group F (P = 0.007). There was no significant difference for AUC for pain between the groups. In conclusion, wounds after flank ovariohysterectomy are significantly more tender than after midline ovariohysterectomy in the cat. This indicates that interactive methods, including wound palpation, must be used to assess postoperative pain and the findings should be appropriately weighted in the overall assessment.     

Pharmacokinetics of difloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications

Pharmacokinetics of difloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of five (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analyzed by a compartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t(1/2beta)) were 17.14 +/- 4.14, 25.79 +/- 8.10, 16.67 +/- 4.04 (pigs) and 6.11 +/- 1.50, 5.64 +/- 0.74, 8.20 +/- 3.12 h (broilers), respectively. After single i.m. and p.o. administration, difloxacin was rapidly absorbed, with peak plasma concentrations (C(max)) of 1.77 +/- 0.66, 2.29 +/- 0.85 (pigs) and 2.51 +/- 0.36, 1.00 +/- 0.21 microg/mL (broilers) attained at t(max) of 1.29 +/- 0.26, 1.41 +/- 0.88 (pigs) and 0.86 +/- 0.4, 4.34 +/- 2.40 h (broilers), respectively. Bioavailabilities (F) were (95.3 +/- 28.9)% and (105.7 +/- 37.1)% (pigs) and (77.0 +/- 11.8)% and (54.2 +/- 12.6)% (broilers) after i.m. and p.o. doses, respectively. Apparent distribution volumes(V(d(area))) of 4.91 +/- 1.88 and 3.10 +/- 0.67 L/kg and total body clearances(Cl(B)) of 0.20 +/- 0.06 and 0.37 +/- 0.10 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), the half-lives of both absorption and distribution(t(1/2ka), t(1/2alpha)) were also determined. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 5 mg/kg given intramuscularly every 24 h in pigs, or administered orally every 24 h at the dosage of 10 mg/kg in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC(90) are <0.25 microg/mL and <0.1 microg/mL respectively.     

Determination of the dosage of clomipramine for the treatment of urine spraying in cats

OBJECTIVE: To determine the optimal dosage of clomipramine for the treatment of urine spraying in cats. DESIGN: Randomized controlled multicenter clinical trial. ANIMALS: 67 neutered cats. PROCEDURE: Cats with a minimum 1-month history of spraying urine against vertical surfaces at least twice per week were randomly assigned to be treated with a placebo or with clomipramine at a dosage of 0.125 to 0.25 mg/kg (0.057 to 0.11 mg/lb), 0.25 to 0.5 mg/kg (0.11 to 0.23 mg/lb), or 0.5 to 1 mg/kg (0.23 to 0.45 mg/lb), p.o., every 24 hours for up to 12 weeks. Owners of all cats were given information on behavioral treatment and environmental modification. RESULTS: Prior to treatment, mean number of urine spraying events ranged from 0.9 to 1.3 urine spraying events/d for the 4 groups, and mean percentage of days with urine spraying events ranged from 62% to 69%. All 3 dosages of clomipramine were associated with significant reductions in frequency of urine spraying. Sedation was the most common adverse effect and was identified in 27 of the 50 cats treated with clomipramine; however, treatment was not discontinued in any cat because of sedation. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the present study suggest that compared with a placebo, clomipramine significantly reduces the frequency of urine spraying in cats in terms of the number of urine spraying events per day and the number of days with urine spraying events. For cats with urine spraying, the recommended initial dosage of clomipramine is 0.25 to 0.5 mg/kg, p.o., every 24 hours.     

Control of urine marking by use of long-term treatment with fluoxetine or clomipramine in cats

OBJECTIVES: To determine whether clomipramine differs from fluoxetine in reducing feline urine marking; whether reduction of marking continues in cats treated >8 weeks; whether recurrence of marking, after abrupt drug withdrawal, is less in cats treated >8 weeks; and whether cats that are successfully treated but resume marking after drug withdrawal can be successfully treated again with the same drug regimen. DESIGN: Positive-controlled, double-masked clinical trial. ANIMALS: 22 neutered cats (2 females, 20 males) > or =1 year old with objectionable urine marking. PROCEDURE: Cats that marked vertically > or =3 times/wk were treated with fluoxetine (1 mg/kg [0.45 mg/lb], q 24 h, PO) or clomipramine (0.5 mg/kg [0.23 mg/lb], q 24 h, PO) for 16 weeks, and efficacy was compared. Recurrence of marking was determined after abrupt withdrawal of fluoxetine at 16 or 32 weeks. Reduction in marking in cats treated with fluoxetine for 8 weeks after returning to marking following drug withdrawal was compared with the initial 8 weeks of successful treatment. RESULTS: Efficacy of fluoxetine and clomipramine was similar. Treatment >8 weeks revealed increasing efficacy in reduction of marking. Return of marking after termination of fluoxetine administration occurred in most cats. Cats successfully treated initially with fluoxetine responded similarly to repeated treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Clomipramine and fluoxetine were equivalent in treating urine marking. Longer treatment increased efficacy. Most cats return to marking after abrupt drug withdrawal. A second course of treatment can be expected to be as effective as the first.     

The effects of clomipramine hydrochloride in cats with psychogenic alopecia: a prospective study

A double-blind, placebo-controlled clinical trial was conducted to determine the efficacy of clomipramine hydrochloride in cats with psychogenic alopecia. Twenty-five cats were randomly assigned to receive clomipramine hydrochloride (0.5 mg/kg orally q 24 hours) or placebo for 56 days. Eleven cats in each group completed the trial. The results of this study showed that clomipramine hydrochloride failed to demonstrate significant changes in the number of grooming bouts, hair regrowth, and the area of alopecia in cats with psychogenic alopecia when compared to a placebo. It was uncertain whether these results reflected a lack of drug efficacy, insufficient treatment duration, or an insufficient number of cases enrolled.     

Pharmacokinetics and safety of penciclovir following oral administration of famciclovir to cats

OBJECTIVE: To investigate penciclovir pharmacokinetics following single and multiple oral administrations of famciclovir to cats. ANIMALS: 8 adult cats. PROCEDURES: A balanced crossover design was used. Phase I consisted of a single administration (62.5 mg, PO) of famciclovir. Phase II consisted of multiple doses of famciclovir (62.5 mg, PO) given every 8 or 12 hours for 3 days. Plasma penciclovir concentrations were assayed via liquid chromatography-mass spectrometry at fixed time points after famciclovir administration. RESULTS: Following a single dose of famciclovir, the dose-normalized (15 mg/kg) maximum concentration (C(max)) of penciclovir (350 +/- 180 ng/mL) occurred at 4.6 +/- 1.8 hours and mean +/- SD apparent elimination half-life was 3.1 +/- 0.9 hours. However, the dose-normalized area under the plasma penciclovir concentration-time curve extrapolated to infinity (AUC(0-->)) during phase I decreased with increasing dose, suggesting either nonlinear pharmacokinetics or interindividual variability among cats. Accumulation occurred following multiple doses of famciclovir administered every 8 hours as indicated by a significantly increased dose-normalized AUC, compared with AUC(0-->) from phase 1. Dose-normalized penciclovir C(max)following administration of famciclovir every 12 or 8 hours (290 +/- 150 ng/mL or 780 +/- 250 ng/mL, respectively) was notably less than the in vitro concentration (3,500 ng/mL) required for activity against feline herpesvirus-1. CONCLUSIONS AND CLINICAL RELEVANCE: Penciclovir pharmacokinetics following oral famciclovir administration in cats appeared complex within the dosage range studied. Famciclovir dosages of 15 mg/kg administered every 8 hours to cats are unlikely to result in plasma penciclovir concentrations with activity against feline herpesvirus-1.     

Use of plasma creatine kinase pharmacokinetics to estimate the amount of excercise-induced muscle damage in Beagles

OBJECTIVE: To assess the effects of moderate exercise on plasma creatine kinase (CK) pharmacokinetics and to estimate exercise-induced muscle damage in dogs. ANIMALS: 6 untrained adult Beagles. PROCEDURE: The study was divided into 3 phases. In phase 1, dogs ran for 1 hour at a speed of 9 km/h, and samples were used to determine the area under the plasma CK activity versus time curve (AUC) induced by exercise. In phases 2 and 3, pharmacokinetics of CK were calculated in dogs during exercise and at rest, respectively. Values for AUC and plasma clearance (CI) were used to estimate muscle damage. RESULTS: At rest, values for Cl, steady-state volume of distribution (Vdss), and mean retention time (MRT) were 0.32+/-0.02 ml/kg of body weight/min, 57+/-173 ml/kg, and 3.0+/-0.57 h, respectively. During exercise, Cl decreased significantly (0.26+/-0.03 ml/kg/min), MRT increased significantly, (4.4+/-0.97 h), and Vdss remained unchanged. Peak of plasma CK activity (151+/-58.8 U/L) was observed 3 hours after completion of exercise. Estimated equivalent amount of muscle corresponding to the quantity of CK released was 41+/-29.3 mg/kg. CONCLUSION AND CLINICAL RELEVANCE: These results revealed that exercise had a minor effect on CK disposition and that the equivalent amount of muscle damaged by moderate exercise was negligible. This study illustrates the relevance for use of the minimally invasive and quantitative pharmacokinetic approach when estimating muscle damage.     

Limited sampling pharmacokinetics of subcutaneous ondansetron in healthy geriatric cats,cats with chronic kidney disease,and cats with liver disease

Ondansetron, a 5‐HT₃ receptor antagonist, is an effective anti‐emetic in cats. The purpose of this study was to compare pharmacokinetics of subcutaneous (SQ) ondansetron in healthy geriatric cats to cats with chronic kidney disease (CKD) or liver disease using a limited sampling strategy. 60 cats participated; 20 per group. Blood was drawn 30 and 120 min following one 2 mg ( mean 0.49 mg/kg , range 0.27–1.05 mg/kg ) SQ dose of ondansetron. Ondansetron concentrations were measured by liquid chromatography coupled to tandem mass spectrometry. Drug exposure represented as area under the curve (AUC) was predicted using a limited sampling approach based on multiple linear regression analysis from previous full sampling studies, and clearance (CL/F) estimated using noncompartmental methods. Kruskal–Wallis anova was used to compare parameters between groups. Mean AUC (ng/mL·h) of subcutaneous ondansetron was 301.4 (geriatric), 415.2 (CKD), and 587.0 (liver). CL/F (L/h/kg) of SQ ondansetron was 1.157 (geriatric), 0.967 (CKD), and 0.795 (liver). AUC was significantly higher in liver and CKD cats when compared to geriatric cats (P < 0.05). CL/F in liver cats was significantly decreased (P < 0.05) compared to geriatric cats. In age‐matched subset analysis, AUC and CL/F in liver cats remained significantly different from geriatric cats.     

Plasma and urine concentrations of marbofloxacin following single subcutaneous administration to cats

The pharmacokinetic properties of marbofoxacin, a third generation fluoroquinolone, were investigated in 12 healthy adult cats after single subcutaneous (SC) administration of 2 mg/kg BW (Part I, n=8 cats) and 4 mg/kg BW (Part II, n=4 cats). In each part of the study blood and urine samples were collected before treatment and thereafter for 5 days. The plasma and urine concentrations of marbofloxacin were determined by HPLC with UV detection. Pharmacokinetic calculations were performed for each treated animal using an open one-compartment-model with first-order elimination after SC dosing. Marbofloxacin in plasma (means): Maximum concentrations (Cmax) of about 1.2 and 3.0 microg/ml were measured 2.3 and 4 hours (tmax) after dosing of 2 and 4 mg/kg BW, respectively. Elimination from the body was low with a total clearance (Cl/F) of approximately 0.1 l/h/kg for both dosages. The half-life (t 1/2) for this process was calculated with 8-10 hours. AUC increased almost proportional when doubling the dose, i.e., 19.77 +/- 6.25 microg * h/ml (2 mg/kg BW) and 51.26 +/- 11.83 microg * h/ml (4 mg/kg BW). Plasma kinetics measured were in accordance with data from literature. Marbofloxacin in urine (means): Maximum drug concentrations were detected 4 and 8 hours after dosing with 70 microg/ml (2 mg/kg BW) and 160 microg/ml (4 mg/kg BW), respectively. Inhibitory effects of the urinary matrix on the antimicrobial activity of the drug were taken into account when performing PK/PD calculations. However, a concentration-dependent bactericidal activity (Cmax/MIC > 8-10) which is claimed for fluoroquinolones was sufficiently met with focus on Escherichia (E.) coli (MIC90 0.5 microg/ml). In the same matrix a threshold value of 1.0 microg/ml was undercut 82 and 116 hours after SC dosing, respectively. Hence, a time-dependent bacteria killing kinetic (T > MIC) which may be of relevance for some Gram-positive germs like Staphylococcus spp. (MIC90 1.0 microg/ml) should be covered, too.     

喹烯酮在鸡体内的代谢及药物动力学研究

以HPLC-MS/MS为定量手段,研究了喹烯酮经静脉注射(2.5 mg/kg)、口服(30 mg/kg)两种给药途径在鸡体内的代谢及药物动力学特征.鸡静脉注射喹烯酮后,血浆中检测到喹烯酮原药和1-脱氧喹烯酮;口服灌注喹烯酮后,血浆中检测到喹烯酮原药和3-甲基喹噁啉-2-羧酸(MQCA).喹烯酮在鸡体内的药动学数据采用统...     

Pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide in domestic cats

The pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide after intravenous (i.v.) and oral (p.o.) administration were evaluated in adult cats. Three treatments were administered: a single i.v. dose of A77 1726 (4 mg/kg), a single oral dose of leflunomide (4 mg/kg), and multiple oral doses of leflunomide (2 mg/kg). Mean pharmacokinetic parameter values after a single i.v. dose of A77 1726 were distribution (A) and elimination (B) intercepts (15.2 μg/mL and 34.5 μg/mL, respectively), distribution and elimination half-lives (1.5 and 71.8 h, respectively), area under the curve (AUC(0 → ∞); 3723 μg*h/mL), mean residence time (MRT; 93 h), clearance (Cl(obs); 1.1 mL/kg/h), and volume of distribution at steady state (Vd(ss); 97 mL/kg). Mean pharmacokinetic parameter values after a single oral dose of leflunomide were absorption and elimination rate constants (0.3 1/h and 0.01 1/h, respectively), absorption and elimination half-lives (2.3 and 59.1 h, respectively), AUC(0 → ∞) (3966 μg*h/mL), and maximum observed plasma concentration (C(max); 38 μg/mL). The bioavailability after a single oral dose of leflunomide was 100%. The mean ± SD A77 1726 concentration that inhibited 50% lymphocytes (EC(50) ) was 16 ± 13.5 μg/mL. The mean ± SD maximum A77 1726 concentration (EC(max)) was 61.0 ± 23.9 μg/mL.     

The pharmacokinetics of clomipramine and desmethylclomipramine in dogs: parameter estimates following a single oral dose and 28 consecutive daily oral doses of clomipramine

Clomipramine is a tricyclic antidepressant that has been recommended for the treatment of canine compulsive disorder. The pharmacokinetics of clomipramine in dogs have not been reported. This study describes the pharmacokinetics of clomipramine and its active metabolite, desmethylclomipramine, in six male dogs. Serial blood samples were collected following both a single oral dose of clomipramine (3 mg/kg) and 28 consecutive daily oral doses (3 mg/kg q 24 h). In addition, 'peak' and 'trough' samples were taken throughout the 28-day dosing period. Plasma was assayed for total (free and protein-bound) clomipramine and desmethylclomipramine, using gas-chromatography with mass spectrometric detection. Various pharmacokinetic parameters were then determined. Following a single dose of clomipramine, time of maximum plasma concentration ( t _max) of clomipramine was 0.75–3.1 h, maximum plasma concentration ( C _max) was 16–310 ng/mL and elimination half-life ( t _1/2el) was 1.2–16 h; t _max of desmethylclomipramine was 1.4–8.8 h, C _max was 21–134 ng/mL and t _1/2el was 1.2–2.3 h. Following multiple dosing, there was a numeric increase in these parameters; t _max of clomipramine was 3–8 h, C _max was 43–222 ng/mL and t _1/2el was 1.2–16 h; t _max of desmethylclomipramine was 1.4–8.8 h, C _max was 21–134 ng/mL and t _1/2el was 1.2–2.3 h. Clinically significant differences between dogs and humans in the pharmacokinetics of oral clomipramine are discussed.     

Pharmacokinetics of sparfloxacin in broiler chicken

1. The pharmacokinetics of sparfloxacin in broiler chicken was investigated following a single intravenous dose of 10 mg/kg and a single oral dose of 20 mg/kg. The pharmacokinetic parameters (AUC(0-24) or C(max)) were integrated with the pharmacodynamic parameter (MIC(90)) to optimize sparfloxacin dosage in chicken. 2. The apparent volume of distribution, total body clearance, mean residence time and elimination half-life following oral administration were 2.411/kg, 4.55 ml/min per kg, 10.54 and 5.94 h, respectively. Oral bioavailability was 61.7%. 3. Sparfloxacin was found to possess clinically useful pharmacokinetic properties. Based on pharmacokinetic/pharmacodynamic integration an oral dose of 20 mg/kg sparfloxacin for every 24 h might be recommended for a successful clinical effect in chickens.     

Disposition of cyclosporine after intravenous and multi-dose oral administration in cats

The aim of this study was to evaluate the disposition of cyclosporine after intravenous (i.v.) and oral administration and to evaluate single sampling times for therapeutic monitoring of cyclosporine drug concentrations in cats. Six adult male cats (clinically intact) were used. Two treatments consisting of a single i.v. cyclosporine (1 mg/kg) and multiple oral cyclosporine (3 mg/kg b.i.d p.o. for 2 weeks) doses. Whole blood cyclosporine concentrations were measured at fixed times by high performance liquid chromatography and pharmacokinetic values were calculated. Mean values for the i.v. data included AUC (7413 ng/mL.h), t1/2 distribution and elimination (0.705 and 9.7 h, respectively), Cmax (1513 ng/mL), and Vd(ss) (1.71 L/kg). Mean values for the oral data included AUC (6243 ng/mL.h), t1/2 of absorption and elimination (0.227 and 8.19 h, respectively), and Cmax (480.0 ng/mL). Bioavailability of orally administered cyclosporine was 29 and 25% on days 7 and 14 respectively. Whole blood comment cyclosporine concentration 2 h after administration (C2) better correlated with AUC on days 7 and 14 than trough plasma concentration (C12). The rate of oral cyclosporine absorption was less than expected and there was substantial individual variation. Therapeutic drug monitoring strategies for cyclosporine in cats should be re-evaluated.     

Comparative pharmacokinetics of intravenous cephalexin in pregnant, lactating, and nonpregnant, nonlactating goats

The aims of this study were to describe and compare the pharmacokinetics of a single dose of cephalexin (10 mg/kg) after its intravenous (i.v.) administration to five goats in three different physiological status: nonpregnant nonlactating (NPNL), pregnant (P) and nonpregnant lactating (L). Blood samples were collected at predetermined times, and plasma concentrations of cephalexin were measured by microbiological assay. Relevant pharmacokinetic parameters were calculated using noncompartmental analysis. Statistical comparison was performed applying the nonparametric anova. No significant differences were found for cephalexin pharmacokinetic parameters between the L and the NPNL group. Median V(dss) was significantly lower in pregnant goats (0.09 [0.07-0.10] L/kg) compared with NPNL goats (0.16 [0.14-0.49] L/kg). Median total Cl and V(dz) were significantly lower in pregnant goats (0.25 [0.19-0.29] L/h·kg and 0.11 [0.10-0.13] L/kg, respectively) than in lactating goats (0.40 [0.32-0.57] L/h·kg and 0.20 [0.14-0.23] L/kg, respectively). Median AUC(0-∞) was significantly higher in pregnant goats (37.79 [34.75-52.10] μg·h/mL) than in lactating goats (25.11 [17.44-31.14] μg·h/mL). Our study showed that even though some pharmacokinetic parameters of cephalexin are altered in pregnant and lactating goats, these differences are unlikely to be of clinical importance; therefore, no dose adjustment would be necessary during pregnancy and lactation.