Pharmacokinetics of indomethacin in sheep after intravenous and intramuscular administration

The pharmacokinetics of indomethacin (1mg/kg) was determined in six adult sheep after intravenous (i.v.) and intramuscular (i.m.) injection. Plasma concentrations were maintained within the therapeutic range (0.3–3.0 μg/mL) from 5 to 50 min after i.v. and from 5 to 60–90 min after i.m. administration. After two trials, indomethacin best fitted an open two-compartment model. The mean (±SD) volumes of distribution at steady state ( V d_ss) were 4.10 ± 1.40 and 4.21 ± 1.93 L/kg and the mean clearance values ( C l_B) were 0.17 ± 0.06 and 0.22 ± 0.12 L/h.kg for i.v. and i.m. routes, respectively. The elimination phase half-lives did not show any significant difference between routes of injection ( t _½β = 17.4 ± 4.6 and 21.25 ± 4.44 h, i.v. and i.m. respectively). After i.m. administration, plasma maximum concentration ( C _max =  1.10 ± 0.68 μg/mL) was reached 10 min after dosing; the absorption phase was fast ( K _ab = 26 ± 18 h-1) and short ( t _½ab = 2.33 ± 1.51 min) and the mean bioavailability was 91.0 ± 32.8%, although there was considerable interanimal variation. In some individuals, bioavailability was higher than 100%. This fact combined with the slower elimination phase after i.m. than after i.v. administration, could be related with enterohepatic recycling.     

Pharmacokinetics of ketamine and its metabolite, norketamine, after intravenous administration of a bolus of ketamine to isoflurane-anesthetized dogs

OBJECTIVE: To determine the pharmacokinetics of ketamine and norketamine in isoflurane-anesthetized dogs. Animals-6 dogs. PROCEDURE: The minimum alveolar concentration (MAC) of isoflurane was determined in each dog. Isoflurane concentration was then set at 0.75 times the individual's MAC, and ketamine (3 mg/kg) was administered IV. Blood samples were collected at various times following ketamine administration. Blood was immediately centrifuged, and the plasma separated and frozen until analyzed. Ketamine and norketamine concentrations were measured in the plasma samples by use of liquid chromatography-mass spectrometry. Ketamine concentration-time data were fitted to compartment models. Norketamine concentration-time data were examined by use of noncompartmental analysis. RESULTS: The MAC of isoflurane was 1.43 +/- 0.18% (mean +/- SD). A 2-compartment model best described the disposition of ketamine. The apparent volume of distribution of the central compartment, the apparent volume of distribution at steady state, and the clearance were 371.3 +/- 162 mL/kg, 4,060.3 +/- 2,405.7 mL/kg, and 58.2 +/- 17.3 mL/min/kg, respectively. Norketamine rapidly appeared in plasma following ketamine administration and had a terminal half-life of 63.6 +/- 23.9 minutes. A large variability in plasma concentrations, and therefore pharmacokinetic parameters, was observed among dogs for ketamine and norketamine. CONCLUSIONS AND CLINICAL RELEVANCE: In isofluraneanesthetized dogs, a high variability in the disposition of ketamine appears to exist among individuals. The disposition of ketamine may be difficult to predict in clinical patients.     

Pharmacokinetics, metabolism and urinary detection time of flunixin after intravenous administration in camels

The pharmacokinetics of flunixin were determined after an intravenous dose of 1.1 mg/kg body weight in six camels and 2.2 mg/kg body weight in four camels. The data obtained (mean ±  SEM) for the low and high dose, respectively, were as follows:
  The elimination half-lives ( t _½β) were 3.76 ± 0.24 and 4.08 ± 0.49 h, the steady state volumes of distribution ( V d_ss) were 320.61 ± 38.53 and 348.84 ± 35.36 mL/kg body weight, total body clearances ( Cl _T) were 88.96 ± 6.63 and 84.86 ± 4.95 mL/h/kg body weight and renal clearances ( Cl _r) were 0.52 ± 0.09 and 0.62 ± 0.18 mL/h/kg body weight. A hydroxylated metabolite of flunixin was identified by gas chromatography/mass spectrometry (GC/MS) under electron and chemical ionization and its major fragmentation pattern was verified by tandem mass spectrometry (GC/MS/MS) using neutral loss, daughter and parent scan modes. The detection times for flunixin and its hydroxylated metabolite in urine after an intravenous (i.v.) dose of 2.2 mg/kg body weight were 96 and 48 h, respectively.     

The pharmacokinetics of ketamine administered intravenously in calves and the modifying effect of premedication with xylazine hydrochloride

Ketamine hydrochloride was administered intravenously to unpremedicated and xylazine-treated calves. The plasma concentrations of ketamine and norketamine were measured at several time intervals after drug administration and the data were fitted to a two-compartment open model. In unpremedicated female calves the distribution and elimination half-lives averaged 6.9 and 60.5 min, respectively. The volume of the central compartment was 1.21 1/kg and the peripheral compartment was 4.04 1/kg. Total body clearance of ketamine averaged 40.4 ml/ min/kg. Premedication with xylazine, whilst not affecting the half-lives signifi-candy, reduced volumes of distribution and the clearance rate of the drug by approximately 50%. The results for the male calves which were premedicated were intermediate between the two groups of female calves.     

Studies on the pharmacokinetics of cisatracurium in anesthetized dogs: in vitro–in vivo correlations

Cisatracurium undergoes primarily temperature and pH-dependent Hofmann elimination in humans. This study was conducted to describe the pharmacokinetics of cisatracurium in anesthetized dogs and determine whether its in vitro degradation rate in plasma is predictive of its in vivo elimination rate, as this is the case in humans. Nine dogs were anesthetized with pentobarbital and administered different bolus doses of cisatracurium in a randomized cross-over design. Arterial blood was collected at frequent intervals after each bolus injection. In vitro degradation rate ( k _{in vitro} ) of cisatracurium was determined in each dog blank plasma. Plasma concentrations were determined by HPLC. Pharmacokinetic analyses were performed using two compartmental models assuming central or both central and peripheral elimination. Mean in vivo terminal elimination rate of cisatracurium (16.4 ± 2.7 min) was twofold faster than mean in vitro degradation rate (32.9 ± 3.7 min) in our dogs. Organ clearance was 6.12 ± 1.69 mL/min·kg and accounted for 56 ± 12% of the total body clearance. Apparent volume of distribution, an exit site-dependent parameter, averaged 212 or 184 mL/kg whether or not peripheral elimination was accounted for in the model. The in vitro rate of degradation in plasma is not of predictive value for the in vivo elimination rate of cisatracurium in anesthetized dogs. Organ clearance plays a more important role in the elimination of cisatracurium in dogs than in humans. Increased biliary excretion and/or presence of renal secretion are potential mechanisms that need to be explored.     

Pharmacokinetics of ketamine following a short intravenous infusion to isoflurane-anesthetized New Zealand White rabbits (Oryctolagus cuniculus)

ObjectiveTo describe the pharmacokinetics of ketamine following a short intravenous (IV) infusion to isoflurane-anesthetized rabbits.Study designProspective experimental study.AnimalsA total of six adult healthy female New Zealand White rabbits.MethodsAnesthesia was induced with isoflurane in oxygen. Following determination of isoflurane minimum alveolar concentration (MAC), the isoflurane concentration was reduced to 0.75 MAC and ketamine hydrochloride (5 mg kg^–1) was administered IV over 5 minutes. Blood samples were collected before and at 2, 5, 6, 7, 8, 9, 13, 17, 21, 35, 65, 125, 215 and 305 minutes after initiating the ketamine infusion. Samples were processed immediately and the plasma separated and stored at –80 °C until analyzed for ketamine and norketamine concentrations using liquid chromatography–mass spectrometry. Compartment models were fitted to the concentration–time data for ketamine and for ketamine plus norketamine using nonlinear mixed-effects (population) modeling.ResultsA three- and five-compartment model best fitted the plasma concentration–time data for ketamine and for ketamine plus norketamine, respectively. For the ketamine only model, the volume of distribution at steady state (Vss) was 3217 mL kg^–1, metabolic clearance was 88 mL minute^–1 kg^–1 and the terminal half-life was 59 minutes. For the model including both ketamine and norketamine, Vss were 3224 and 2073 mL kg^–1, total metabolic clearance was 107 and 52 mL minute^–1 kg^–1 and terminal half-lives were 52 and 55 minutes for the parent drug and its metabolite, respectively.Conclusions and clinical relevanceThis study characterized the pharmacokinetics of ketamine and norketamine in isoflurane-anesthetized New Zealand White rabbits following short IV infusion. The results obtained herein will be useful to determine ketamine infusion regimens in isoflurane-anesthetized rabbits.     

In vitro kinetics of hepatic albendazole sulfoxidation in channel catfish (Ictalurus punctatus), tilapia (Oreochromis sp.), rainbow trout (Oncorhynchus mykiss) and induction of EROD activity in ABZ-dosed channel catfish

Liver microsomes from market-size ( n  = 6) rainbow trout, channel catfish and tilapia were used to investigate in vitro biotransformation kinetics of albendazole (ABZ). ABZ was transformed to a single metabolite, ABZ sulfoxide (ABZ-SO). Catfish displayed the highest maximal velocity ( V _max = 264.0 ± 58.6 pmols ABZ-SO/min/mg protein) followed by tilapia (112.3 ± 8.2) and rainbow trout (73.3 ± 10.3). V _max in catfish was significantly different ( P  < 0.05) from the other two species. Michaelis–Menten constant ( K _m) values (μ m ) varied significantly among the species: rainbow trout (3.9 ± 0.5), tilapia (9.2 ± 1.7) and catfish (22.0 ± 3.2). However, V _max/ K _m ratios showed no difference among the three species, making them equally efficient performing this phase I biotransformation reaction. In a second series of experiments, channel catfish ( n  = 6 per treatment) were dosed in vivo with gel-food containing ABZ (10 mg/kg, p.o.). Fish were killed at 24, 48, 72 and 120 h after dosage. Control fish were fed ABZ-free feed. Induction of ethoxyresorufin-o-deethylase activity was significant ( P  < 0.05) in all ABZ-dosed treatments as compared with controls.     

Pharmacokinetics of tramadol, and its metabolite O-desmethyl-tramadol, in cats

Tramadol is an analgesic agent and is used in dogs and cats. Tramadol exerts its action through interactions with opioid, serotonin and adrenergic receptors. The opioid effect of tramadol is believed to be, at least in part, related to its metabolite, O-desmethyl-tramadol. The pharmacokinetics of tramadol and O-desmethyl-tramadol were examined after intravenous (i.v.) and oral administration of tramadol to six cats. A two-compartment model (with first-order absorption in the central compartment for the oral administration) with elimination from the central compartment best described the disposition of tramadol in cats. After i.v. administration, the apparent volume of distribution of the central compartment, the apparent volume of distribution at steady-state, the clearance, and the terminal half-life (mean +/- SEM) were 1553+/-118 mL/kg, 3103+/-132 mL/kg, 20.8+/-3.2 mL/min/kg, and 134+/-18 min, respectively. Systemic availability and terminal half-life after oral administration were 93+/-7% and 204+/-8 min, respectively. O-desmethyl-tramadol rapidly appeared in plasma following tramadol administration and had terminal half-lives of 261+/-28 and 289+/-19 min after i.v. and oral tramadol administration, respectively. The rate of formation of O-desmethyl-tramadol estimated from a model including both tramadol and O-desmethyl-tramadol was 0.014+/-0.003/min and 0.004+/-0.0008/min after i.v. and oral tramadol administration, respectively.     

Plasma pharmacokinetics of ranitidine HCl in foals

Plasma pharmacokinetics of ranitidine HCl were investigated after intravenous (i.v.) and oral (p.o.) administration of drug to six healthy foals. Twelve- to sixteen-week-old foals received 2.2 mg ranitidine/kg i.v. and 4.4 mg ranitidine/kg p.o. Concentrations of ranitidine were determined using normal phase high performance liquid chromatography. Plasma concentrations of ranitidine HCl declined from a mean of 3266 ng/mL at 5 min to 11 ng/mL at 720 min after administration. The profile of the plot of concentrations of ranitidine HCl vs. time was best described by a two-exponent equation for two foals; data for the remaining four foals were best described by a three-exponent equation. Mean values for model-independent values were: apparent volume of distribution ( V d_ss) = 1.46 L/kg; area under the curve ( AUC ) = 16 7442 ng·min/mL; area under the moment curve ( AUMC ) = 18 068 221 ng·min²/mL; mean residence time ( MRT ) = 108.9 min; and clearance ( Cl ) = 13.3 mL/min.kg. Following p.o. administration, a two-exponent equation best described data for five foals; data for the remaining foal were best described by a three-exponent equation. Mean values of the pharmacokinetic values from the p.o. study include: AUC  = 12 6413 ng·min/mL; AUMC  = 18 039 825 ng·min²/mL; mean absorption time ( MAT ) = 32.0 min; observed time to maximum plasma concentration ( T _max) = 57.2 min; maximum observed plasma concentration ( C _max) = 635.7 ng/mL; and bioavailability ( F ) = 38%.     

Single and multiple-dose pharmacokinetics of tepoxalin and its active metabolite after oral administration to rabbits (Oryctolagus cuniculus)

The anti-inflammatory agent, tepoxalin, was administered to eight healthy 6-month-old female New Zealand white rabbits once daily at an oral dose of 10 mg/kg. Blood samples were obtained immediately before and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h postadministration on days 1 and 10. Tepoxalin and its active metabolite, RWJ 20142, concentrations were determined in plasma by use of high-performance liquid chromatography with mass spectrometry. C _max of the parent compound was reached between 3 and 8 h of drug administration, with a harmonic mean t _1/2 of 3.6 h. Peak tepoxalin plasma concentrations were 207 ± 49 ng/mL. After oral administration, the metabolite RWJ 20142 achieved C _max in plasma 2–8 h after administration, with a t _1/2 of 1.9–4.8 h (harmonic mean 2.8 h). Peak plasma concentrations of RWJ 20142 on day 1 were 2551 ± 1034 ng/mL.     

Pharmacokinetics of phenylbutazone in plasma and milk of lactating dairy cows

Phenylbutazone was administered intravenously (i.v.) to a group of four lactating cows at a dosage of 6 mg/kg body weight. Whole plasma, protein-free plasma and milk were analysed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a non compartmental method. In regards to whole plasma data, the mean volume of distribution at steady state ( V _ss), was 147 mL/kg body weight, with a mean (± SEM) terminal elimination half-life ( t _1/2) of 40 ± 6 h. The mean clearance ( Cl ) was 3 mL/h/kg body weight. The V _ss as determined from the protein-free plasma fraction was 50 021 mL/kg body weight. This larger V _ss of free phenylbutazone compared to total plasma phenylbutazone was attributed to a high degree of plasma protein binding, as well as the greater penetration of free phenylbutazone into tissues. The mean t _1/2 of free phenylbutazone was 39 ± 5 h. This similarity to the t _1/2 estimated from total plasma phenylbutazone data is attributed to an equilibrium between free and plasma phenylbutazone during the terminal elimination phase. Mean t _1/2 as determined from milk, applying a urinary excretion rate model, was 47 ± 4 h. Milk clearance of phenylbutazone was 0.009 mL/h/kg body weight, or about 0.34% of total body clearance. Furthermore, evidence suggests that phenylbutazone either binds to milk proteins, or is actively transported into milk, as its concentration in milk was greater than that predicted due to a simple partitioning from plasma into milk.     

Pharmacokinetics of imidocarb in normal dogs and goats

The pharmacokinetics of imidocarb were studied in seven mongrel dogs and eight crossbred goats. An intravenous bolus dose (4 mg/kg) of 12% imidocarb dipropionate solution wasinjected into the cephalic vein in dogs and the jugular vein in goats. The plasma concentration of imidocarb was measured by spectro-photometry. The experimental data were analysed using a two-compartment open model. The apparent volume of the central compartment was significantly higher ( P <0.01) in dogs than in goats. The significantly larger ( P <0.05) apparent specific volume of distribution in goats than in dogs may be attributed to passive diffusion followed by ion trapping of the drug in rumen fluid. Neither the half-life nor body clearance differed significantly between dogs ( t _1/2, 207 ± 45 min; Cl_B , 1.47 ± 0.38 ml/min kg) and goats ( t _1/2, 251 ± 94 min; Cl_B , 1.62 ± 0.50 ml/min kg). While almost 80% of the dose had been eliminated at 8 h in. both species, the high ratio of the imidocarb level in the peripheral-to-central compartment in goats suggests that a prolonged period may be required for complete elimination of the drug.     

The effects of pentoxifylline infusion on plasma 6-keto-prostaglandin F1α and ex vivo endotoxin-induced tumour necrosis factor activity in horses

Pentoxifylline (7.5 mg/kg) was bolused intravenously to eight healthy horses and was immediately followed by infusion (1.5 mg/kg/h) for 3 h. Clinical parameters were recorded and blood samples were collected for 24 h. Plasma was separated and concentrations of pentoxifylline, its reduced metabolite I, and 6-keto-prostaglandin F_1α were determined. Heparinized whole blood was also incubated ex vivo with 1 ng Escherichi coli endotoxin/mL blood for 6 h before determination of plasma tumour necrosis factor activity. The peak plasma concentrations of pentoxifylline and metabolite I occurred at 15 min after bolus injection and were 9.2± 1.4 and 7.8± 4.3 μg/mL, respectively. The half-life of elimination ( t _½β) of pentoxifylline was 1.44 h and volume of distribution ( V d_area) was 0.94 L/kg. The mean plasma concentration of 6-keto-prostaglandin F_1α increased over time, with a significant increase occurring 30 min after the bolus administration. Ex vivo plasma endotoxin-induced tumour necrosis factor activity was significantly decreased at 1.5 and 3 h of infusion. These results indicate that infusion of pentoxifylline will increase 6-keto-prostaglandin F_1α and significantly suppress endotoxin-induced tumour necrosis factor activity in horses during the period of infusion.     

Pharmacokinetic parameters and milk concentrations of ketoprofen after administration as a single intravenous bolus dose to lactating goats

Six clinically normal lactating does were administered ketoprofen (2.2 mg/kg intravenously (i. v.)). Blood and milk samples were collected prior to and for 24 h after drug administration. Drug concentrations in serum and milk were determined by high performance liquid chromatography. Pharmacokinetic parameters from each goat were combined to obtain mean estimates (mean ± SD) of half-life of elimination ( t _½β) of 0.32 ± 0.14 h, systemic clearance ( Cl ) of 0.74 ± 0.12 L/kg· h, and volume of distribution at steady state ( V _ss) of 0.23 ± 0.051 L/kg. In milk, ketoprofen was unmeasurable by the method employed (level of detection 25 ng/mL) for all samples.     

The pharmacokinetics of furosemide in anaesthetized horses after bilateral ureteral ligation

The pharmacokinetics of furosemide were investigated in anaesthetized horses with bilateral ureteral ligation (BUL) with ( n  = 5) or without ( n  = 5) premedication with phenylbutazone. Horses were administered an intravenous (i.v.) bolus dose of furosemide (1 mg/kg) 6090 min after BUL. Plasma samples collected up to 3 h after drug administration were analysed by a validated high performance liquid chromatography method. Median plasma clearance ( CL _p) of furosemide in anaesthetized horses with BUL was 1.4 mL/min/kg. Apparent steady state volume of distribution ( V d_ss) ranged from 169 to 880 mL/kg and the elimination half life ( t _½) ranged from 83 min to 209 h.   No differences in plasma concentration or kinetic parameter estimates were observed when phenylbutazone was administered before furosemide administration. BUL markedly reduces the elimination of furosemide in horses and models the potential effects that severe changes in kidney function may have on drug kinetics in horses.     

A Single Sample Method for Evaluating 51Chromium-Ethylene Diaminic Tetraacetic Acid Clearance in Normal and Hyperthyroid Cats

Background: Chronic kidney failure is frequently seen in middle-aged and elderly cats. ⁵¹Chromium-ethylene diaminic tetraacetic acid (⁵¹Cr-EDTA) clearance and single blood sample (SBS) method are used in several species to estimate the glomerular filtration rate (GFR).
Hypothesis: The hypothesis of this study was that ⁵¹Cr-EDTA clearance could be determined using an SBS method in normal and hyperthyroid cats.
Animals: Forty-six cats were included in this study, with an average age of 9.5 years. Of these cats, 27 had hyperthyroidism; 19 were healthy.
Methods: After IV injection of ⁵¹Cr-EDTA (average dose: 4.25 MBq), 7 blood samples were obtained between 5 and 240 minutes. Reference clearance was calculated in mL/min and mL/min/kg body weight, using a 2-compartment model. Optimal time for clearance measurement with SBS was then determined by systematically comparing each individual plasma concentration to the reference multisample clearance.
Results: The average reference plasma clearance of ⁵¹Cr-EDTA for all cats was 14.9 mL/min (3.7 mL/min/kg). The clearance in hyperthyroid cats averaged 16.4 mL/min (4.3 mL/min/kg) and in normal cats averaged 10.3 mL/min (2.4 mL/min/kg).
The optimal time for the SBS was 48 minutes after injection of tracer ⁵¹Cr-EDTA ( R ²= 0.9414), giving the following converting equation: clearance = (0.0066 × DV_{48 minutes}) – 0.9277 (in mL/min).
Conclusions and Clinical Importance: In this study, the single sample ⁵¹Cr-EDTA clearance method was used to estimate the global GFR in cats. The method identified differences in clearance between normal and hyperthyroid cats. The optimal time for an SBS was 48 minutes.     

Pharmacokinetics and anesthetic activity of eugenol in male Sprague-Dawley rats

Eugenol, the principle chemical constituent of clove oil, has recently been evaluated for its anesthetic and analgesic properties in fish and amphibians. The objective of this study was to determine the pharmacokinetic (PK) and anesthetic activity of eugenol in rats. Male Sprague–Dawley rats received single i.v. doses of eugenol (0, 5, 10, 20, 40 and 60 mg/kg) and anesthetic level was evaluated with the withdrawal reflex. For the 20 mg/kg dose level, blood and urinary samples were collected over 1 h for the PK assessment. Plasma and blood concentrations of eugenol, as well as metabolite identification in urine, were determined using a novel dansyl chloride derivatization method with liquid chromatography mass spectrometry (LC/MS/MS). PK parameters were calculated using noncompartmental methods. Eugenol-induced loss of consciousness in a dose-dependent manner, with mean (±SEM) recovery in reflex time of 167 ± 42 sec observed at the highest dose level. Mean systemic clearance ( Cl ) in plasma and blood were 157 and 204 mL/min/kg, respectively. Glucuronide and sulfate conjugates were identified in urine. Overall, eugenol produced a reversible, dose-dependent anesthesia in male Sprague–Dawley rats.     

Transplacental exchange of moxidectin after maternal or fetal intravenous administration in sheep

The transplacental exchange of moxidectin after maternal or fetal intravenous (i.v.) administration was studied using the chronically catheterized fetal sheep model. Nine pregnant Suffolk Down sheep of 65.7 ± 5.9 kg body weight (bw) were surgically prepared to insert polyvinyl catheters in the fetal femoral artery and vein and amniotic sac. The ewes were randomly assigned to two experimental groups. In group 1 (maternal injection) five ewes were treated with an i.v. bolus of 0.2 mg of moxidectin/kg bw. In group 2, (fetal injection) an i.v. bolus of 1 mg of moxidectin was administered to the four fetuses by femoral vein catheters. Maternal and fetal blood and amniotic fluid samples were taken before and after moxidectin administration for a 144 h post-treatment period. Samples were analyzed by liquid chromatography. A noncompartmental pharmacokinetic analysis was performed and statistical differences were determined by mean of parametric and nonparametric statistical tests. Pharmacokinetic differences observed in maternal variables were shorter elimination half-life and mean residence time compared with values previously reported for ivermectin. Drug diffusion from maternal to fetal circulation ( AUC _{0– t}  = 232.6 ± 72.5 ng·h/mL) was statistically not different ( P =  0.09) compared with fetal to maternal diffusion ( AUC _{0– t} = 158.0 ± 21.6 ng·h/mL). Fetuses showed significantly ( P  =   0.008) lower drug body clearance values compared with those observed in the maternal side. Considering the observed transplacental passages between materno-fetal or feto-maternal circulations, we conclude that the placental barrier is not effective in preventing the moxidectin diffusion between mother and fetus.     

Pharmacokinetic-pharmacodynamic modelling of meperidine in goats (II): modelling

Simultaneous pharmacokinetic-pharmacodynamic (PK-PD) models of meperidine in Soats were established by utilizing the P₃ wave of the cerebral evoked potentials as an analgesic measurement. An effect compartment linked to the central compartment was postulated in the models. The hypothetical drug amount in the effect compartment was related to the observed analgesia through the Hill equation. After intramuscular (i. m., n = 16) and intravenous (i. v., n = 13) dosing (5 mg/kg), the elimination rate constants of meperidine in the effect compartment ( K _eO) were 0.3744 ± 0.2546 and 0.1123 ± 0.0428 min^-1, drug concentrations in the effect compartment generating half maximal analgesia (EC₍₅₀₎) were 0.70 ± 0.33 and 0.41 ± 0.26 μg/ml, the maximal effects (E_max) were 89.63 ± 15.63 and 85.92 ± 9.64%, and the Hill coefficients (S) were 2.61 ± 1.21 and 2.37 ± 1.15, respectively. K _eO and EC₍₅₀₎ with i.m. dosing were significantly greater than with i.v. injection. However, administration route had no influence on S, E_max and the total amount of effect ( AUE ). The predicted peak effect (E_max^) of 64.44 ± 14.64 and 66.02 ± 11.51% were achieved at 14.7 ± 7.4 and 8.5 ± 2.2 min after i.m. and i.v. dosing, respectively. Peak analgesia appeared much later than peak plasma concentration, but simultaneously with peak CSF level both after i.m. and i.v. dosing. An obvious hysteresis was demonstrated between plasma concentration and analgesic effect. This study demonstrates that meperidine analgesia can be predicted using a PK-PD model, but not by PK data alone. Both i.m. and i.v. administration routes were evaluated kinetically and dynamically.     

Effect of experimental renal impairment on disposition of marbofloxacin and its metabolites in the dog

The pharmacokinetics of marbofloxacin was studied in eight healthy female Beagle dogs before and after moderate renal impairment was induced experimentally. A single intravenous (i.v.) administration and repeated administration for 8 days (2 mg/kg, once-a-day) of marbofloxacin were studied. Renal impairment was induced by a right kidney nephrectomy and electrocoagulation of the left kidney. An increase ( P  < 0.001) in the plasma concentrations of urea (from 3.8 ± 0.7 to 9.8 ± 2.1 mmol/L) and creatinine (from 78.8 ± 3.4 to 145.8 ± 22.3 μmol/L), and a significant decrease (2.9 ± 0.3 vs 1.5 ± 0.2 mL/kg/min) ( P  < 0.001) in glomerular filtration rate were observed in the renal-impaired dogs. The clearance of marbofloxacin was slightly decreased after the induction of renal failure (1.6 ± 0.2 to 1.4 ± 0.1 mL/kg/min) ( P  < 0.05), but no significant variation of volume of distribution at steady state ( V _ss) and mean residence time ( MRT ) was observed after intravenous administration of marbofloxacin ( P > 0.05). Following oral administration of marbofloxacin, an increase in total area under the concentration time curve ( AUC ) was observed after renal failure (from 10372 ± 1710 to 11459 ± 1119 mg.min/L) ( P  < 0.05), but indices of accumulation were not modified. An increase ( P  < 0.01) in the AUC of N-oxide-marbofloxacin was observed after surgery. In conclusion, renal impairment has no biologically relevant influence on marbofloxacin disposition and there is no need for dosage adjustment of marbofloxacin in dogs with mild renal impairment.