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1.
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.  相似文献   

2.
OBJECTIVE: To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. ANIMALS: 6 healthy Greyhounds, 3 male and 3 female. PROCEDURES: Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 +/- 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software. RESULTS: Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds. CONCLUSIONS AND CLINICAL RELEVANCE: Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.  相似文献   

3.
In this study, we investigated the effect of multiple oral dosing of ketoconazole (KTZ) on pharmacokinetics of quinidine (QN), a CYP3A substrate with low hepatic clearance, after i.v. and oral administration in beagle dogs. Four dogs were given p.o. KTZ for 20 days (200 mg, b.i.d.). QN was administered either i.v. (1 mg/kg) or p.o. (100 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. Multiple oral dosing of KTZ decreased significantly alpha and beta, whereas increased t(1/2beta), V(1), and k(a). The KTZ treatment also decreased significantly both total body clearance (Cl(tot)) and oral clearance (Cl(oral)). No significant change in bioavailability was observed in the presence of KTZ. Co-administration of KTZ increased C(max) of QN to about 1.5-fold. Mean resident time after i.v. administration (MRT(i.v.)), and after oral administration (MRT(p.o.)) of QN were prolonged to about twofold, whereas mean absorption time (MAT) was decreased to 50%. Volume of distribution at steady state (V(d(ss))) of QN was unchanged in the presence of KTZ. These alterations may be because of a decrease in metabolism of QN by inhibition of KTZ on hepatic CYP3A activity. In conclusion, multiple oral dosing of KTZ affected largely pharmacokinetics of QN after i.v. and oral administration in beagle dogs. Therefore, KTZ at a clinical dosing regimen may markedly change the pharmacokinetics of drugs primarily metabolized by CYP3A with low hepatic clearance in dogs. In clinical use, much attention should be paid to concomitant administration of KTZ with the drug when given either p.o. or i.v.  相似文献   

4.
Gentamicin pharmacokinetics in diabetic dogs   总被引：1，自引：0，他引：1  
Reduction of the prolonged terminal elimination phase of gentamicin may be caused by diabetes mellitus, irrespective of the model of diabetes. To test this hypothesis, five normal dogs, three dogs with alloxan-induced diabetes mellitus, and four dogs with naturally occurring diabetes mellitus (all of which were given exogenous insulin to control hyperglycemia) were given 4.4 mg/kg gentamicin intravenously. Serum pharmacokinetics were analyzed using non-compartmental pharmacokinetics assuming a sum of exponential terms. Gentamicin pharmacokinetics during the first 8 h were the same in normal and diabetic dogs. Over 7 days, MRT in normal dogs (5830 +/- 2970 min, mean +/- SD) was longer (P less than 0.01) than in diabetic dogs (136 +/- 164 min). In diabetic dogs, Cls was greater (3.01 +/- 0.86 ml/min/kg) than in normal dogs (1.45 +/- 0.11 ml/min/kg; P less than 0.01), whereas Vd(ss) was smaller in diabetic dogs (0.405 +/- 0.508 l/kg) than in normal dogs (8.56 +/- 4.48 l/kg; P less than 0.01). Serum gentamicin concentrations were less than 0.020 microgram/ml by 2 days in all of the diabetic dogs, but were 0.048 +/- 0.018 microgram/ml at 7 days in normal dogs. Thus, diabetes mellitus, either induced by alloxan administration or naturally occurring, abolished the terminal elimination phase of gentamicin disposition in a non-rodent species.  相似文献   

5.
The influence of pretreatment with ketoconazole [cytochrome P450 3A (CYP3A) + P-glycoprotein (P-gp) inhibitor], elacridar (selective P-gp inhibitor) and rifampicin (CYP3A + P-gp inducer) on oral morphine pharmacokinetics and pharmacodynamics was investigated in experimental dogs. Seven beagles were used in a four-way crossover design. Morphine hydrochloride was administered orally (2.5 mg/kg) alone (control group CON) or after pretreatment with ketoconazole (group KETO), elacridar (group ELA) or rifampicin (group RIF). Morphine plasma concentrations were analysed by liquid chromatography-tandem mass spectrometry. Sedation scores (none, mild, moderate or severe) were evaluated subjectively. Dogs were significantly (P < 0.05) more sedated after ketoconazole pretreatment. There were no significant differences between group CON and the other pretreatment groups in pharmacokinetic parameters taking both sexes into account. Sex differences were apparent in some pharmacokinetic parameters of morphine. The area under the plasma concentration time curve (AUC(0-∞) ) was significantly higher, and the total body clearance was significantly lower in male compared to female dogs in all treatment groups. Ketoconazole, rifampicin and elacridar pretreatment had no significant effects on morphine pharmacokinetics, although dogs in the ketoconazole group showed higher sedation scores.  相似文献   

6.
After single oral administration of ketoconazole (30 mg/kg bodyweight [bwt]) in 50 ml of corn syrup to a healthy mare, the drug was not detected in serum. Ketoconazole in 0.2 N HC1 was administered intragastrically to six healthy adult horses in five consecutive doses of 30 mg/kg bwt at 12 h intervals. Ketoconazole concentrations were measured in serum, synovial fluid, peritoneal fluid, cerebrospinal fluid (CSF), urine and endometrium. Mean peak serum ketoconazole concentration was 3.76 micrograms/ml at 1.5 to 2 h after intragastric administration. Mean peak synovial concentration was 0.87 micrograms/ml 3 h after the fifth dose. Similarly, mean peritoneal concentration peaked 3 h after the fifth dose at 1.62 micrograms/ml. Mean endometrial concentrations peaked at 2.73 micrograms/ml 2 h after the fifth dose. Ketoconazole was detected in the CSF of only one of the six mares at a concentration of 0.28 micrograms/ml 3 h after the fifth dose. The highest measured concentration of ketoconazole in urine was 6.15 micrograms/ml 2 h after the fifth dose. A single intravenous injection of ketoconazole (10 mg/kg bwt) was given to one of the six mares; the overall elimination rate constant was estimated at 0.22/h and bioavailability after oral administration was 23 per cent.  相似文献   

7.
The purpose of this study was to compare the pharmacokinetics of two highly protein‐bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy greyhound dogs (three males and three females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry, and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL·min/kg) was faster than buprenorphine (10.3 mL·min/kg). The terminal half‐life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including octanol–water partition coefficient and pKa, the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95–98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs.  相似文献   

8.
Plasma pharmacokinetics and urine concentrations of meropenem in ewes   总被引：1，自引：0，他引：1  
The pharmacokinetics of meropenem was studied in five ewes after single i.v. and i.m. dose of 20 mg/kg bw. Meropenem concentrations in plasma and urine were determined using microbiological assay method. A two-compartment open model was best described the decrease of meropenem concentration in plasma after an i.v. injection. The drug was rapidly eliminated with a half-life of elimination ( t 1/2 β ) of 0.39 ± 0.30 h. Meropenem showed a small steady-state volume of distribution [ V d(ss)] 0.055 ± 0.09 L/kg. Following i.m. injection, meropenem was rapidly absorbed with a t 1/2ab of 0.25 ± 0.04 h. The peak plasma concentration ( C max) was 48.79 ± 8.83  μ g/mL was attained after 0.57 ± 0.13 h ( t max). The elimination half-life ( t 1/2el) of meropenem was 0.71 ± 0.12 h and the mean residence time ( MRT ) was 1.38 ± 0.26 h. The systemic bioavailability (F) after i.m. injection was 112.67 ± 10.13%. In vitro protein-binding percentage of meropenem in ewe's plasma was 42.80%. The mean urinary recoveries of meropenem over 24 h were 83% and 91% of the administered dose after i.v. and i.m. injections respectively. Thus, meropenem is likely to be efficacious in the eradication of many urinary tract pathogens in sheep.  相似文献   

9.
The purpose of the study was to compare the pharmacokinetics of amikacin administered i.v., to Greyhound and Beagle dogs and determine amikacin pharmacokinetics administered subcutaneously to Greyhounds. Amikacin was administered i.v. at 10 mg/kg to six healthy Greyhounds and six healthy Beagles. The Greyhounds also received amikacin, 10 mg/kg s.c. Plasma was sampled at predetermined time points and amikacin concentrations determined by a fluorescence polarization immunoassay (FPIA).
The volume of distribution was significantly smaller in Greyhounds (mean = 176.5 mL/kg) compared to Beagles (234.0 mL/kg). The C 0 and AUC were significantly larger in Greyhounds (86.03 μg/mL and 79.97 h·μg/mL) compared to Beagles (69.97 μg/mL and 50.04 h·μg/mL). The plasma clearance was significantly lower in Greyhounds (2.08 mL/min/kg) compared to Beagles (3.33 mL/min/kg). The fraction of the dose absorbed after s.c. administration to Greyhounds was 0.91, the mean absorption time was 0.87 h, and the mean maximum plasma concentration was 27.40 μg/mL at 0.64 h.
Significant differences in the pharmacokinetics of amikacin in Greyhounds indicate it should be administered at a lower dose compared to Beagles. The dose in Greyhounds to achieve a C max: AUC  ≥ 8 for bacteria (with an MIC  ≤ 4 μg/mL) is 12 mg/kg q24 h compared to 22 mg/kg q24 in Beagles.  相似文献   

10.
OBJECTIVE: To evaluate the inhibitory potency of ketoconazole (KTZ) on the metabolic activities of isozymes of cytochrome P-450 (CYP) in dogs. ANIMALS: 4 healthy 1-year-old male Beagles. PROCEDURE: Hepatic microsomes were harvested from 4 dogs after euthanasia. To investigate the effects of KTZ on CYP metabolic activities, 7-ethoxyresorufin, tolbutamide, bufuralol, and midazolam hydrochloride were used as specific substrates for CYP1A1/2, CYP2C21, CYP2D15, and CYP3A12, respectively. The concentrations of metabolites formed by CYP were measured by high-performance liquid chromatography, except for the resorufin concentrations that were measured by a fluorometric method. The reaction velocity-substrate concentration data were analyzed to obtain kinetic variables, including maximum reaction velocity, Michaelis-Menten constant, and inhibitory constant (Ki). RESULTS: KTZ competitively inhibited 7-ethoxyresorufin O-deethylation and midazolam 4-hydroxylation; it noncompetitively inhibited tolbutamide methylhydroxylation. Bufuralol 1'-hydroxylation was inhibited slightly by KTZ. The mean Ki values of KTZ were 10.6+/-6.0, 170+/-2.5, and 0.180+/-0.131 microM for 7-ethoxyresorufin O-deethylation, tolbutamide methylhydroxylation, and midazolam 4-hydroxylation, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, KTZ at a therapeutic dose may change the pharmacokinetics of CYP3A12 substrates as a result of inhibition of their biotransformation. Furthermore, no influence of KTZ on the pharmacokinetics of CYP1A1/2, CYP2C21, and CYP2D15 substrates are likely. In clinical practice, adverse drug effects may develop when KTZ is administered concomitantly with a drug that is primarily metabolized by CYP3A12.  相似文献   

11.
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.  相似文献   

12.
Intravenous (IV) levetiracetam (LEV) is available for humans for bridge therapy when the oral route is unavailable. We investigated the safety and pharmacokinetics of LEV administered intramuscularly (IM), IV, and orally to dogs.
Six Hound dogs received 19.5–22.6 mg/kg of LEV IM, IV and orally with a wash-out period in between. All dogs received 500 mg LEV orally and 5 mL of 100 mg/mL LEV IM. Three dogs received 500 mg of LEV IV and three dogs received 250 mg LEV IV with 250 mg given perivascularly to approximate extravasation. Safety was assessed using a pain scale at time of IM administration and histopathological examination 24 h to 5 days after injection.
Intravenous LEV half-life was 180 ± 18 min. Bioavailability of IM LEV was 100%. Mean time to Tmax after IM was 40 ± 16 min. The mean Cmax IM was 30.3 ± 3 μg/mL compared to the C0 of 37 ± 5 μg/mL for IV. Mean inflammation score (0–4 scale) for IM LEV was 0.28 and for saline 0.62. Extravasation did not cause tissue damage.
Parenteral LEV is well tolerated and appears safe following IM and IV injections in dogs. Parenteral LEV should be evaluated for use in dogs with epilepsy.  相似文献   

13.
In this study the pharmacokinetics and renal safety of gentamicin in healthy dogs was investigated after multiple dosing. Six adult male dogs received once-daily gentamicin (6 mg/kg) intramuscularly for 5 days. Serial blood samples were taken on days 1 and 5 of treatment, and at predose, 1 and 6 h on days 2, 3 and 4. Urinalysis, hematology and serum biochemistry evaluation were carried out before, 7 and 14 days after the first gentamicin administration. Mean value of the main pharmacokinetic parameters were: AUC (microg.h/mL), 97.4 and 100.2; terminal half-life (harmonic mean), 0.76 and 1.01 h; ClB/F (mL/min.kg), 1.24 and 1.10; VD(area)/F (L/kg), 0.084 and 0.10; MRT (h), 1.48 and 1.77; Cmax (microg/mL), 54.5 and 49.2; tmax (h), 0.40 and 0.48 for the first and last dose, respectively. Accumulation was determined as R1 = 0.97 and R2 = 1.22. Mean trough gentamicin serum concentrations were 0.06, 0.07, 0.09, 0.1 and 0.1 microg/mL for the first, second, third, fourth and fifth dose, respectively. Statistically significant increases (P < 0.05) were found for last dose MRT and fourth and fifth trough gentamicin serum concentrations. Laboratory tests detected a slight increase in serum creatinine and urea nitrogen concentrations (one dog), decreased specific urine gravity (one dog) and presence of few granular casts (two dogs). It is concluded that once-daily administration of gentamicin may provide adequate serum levels to treat most susceptible gram-negative infections with little or no nephrotoxicity in dogs.  相似文献   

14.
We examined the effects of ofloxacin (OFX) and norfloxacin (NFX) on theophylline (TP) pharmacokinetics in dogs. OFX, as a noncompetitive and mechanism-based inhibitor, and NFX, as a noncompetitive inhibitor, were orally administered (5 mg/kg) for a single dose or multiple doses (12 hourly for 3 days). TP (5 mg/kg, i.v) was injected at 2 h after the final dose of the fluoroquinolones (FQs). The same dose of TP was injected (i.v) 3 weeks before the start of FQs treatment for control. Multiple doses of OFX significantly reduced the total body clearance (Cl(B)) of TP from 0.117 to 0.085 L/h/kg, although a single dose did not change it. Neither a single dose nor multiple doses of NFX changed the TP pharmacokinetics. Plasma NFX concentrations increased after multiple doses. Those of OFX also increased but were still two orders of magnitude below the K(i) for noncompetitive inhibition of CYP1A in dogs. Time-dependent reduction in Cl(B) of TP suggests that mechanism-based inhibition of OFX was the major mode to decrease Cl(B) of TP. The mechanism-based inhibition may result in substantial inhibition of CYP1A activities in clinical conditions.  相似文献   

15.
The pharmacokinetics of ampicillin in dogs was determined after intravenous (i.v.) bolus and constant rate infusion. Ampicillin was administered to six beagle dogs as an i.v. bolus at 20 mg/kg and as a constant rate i.v. infusion (CRI) at 20 mg/kg during 8 h (0.042 mL/min/kg) in Ringer's lactate (Hartmann's) solution. The concentrations were determined by an LC/MS/MS method. After i.v. bolus, ampicillin total body clearance, apparent volume of distribution at steady‐state, mean residence time (MRT), and half‐life were 4.53 ± 0.70 mL/min/kg, 0.275 ± 0.044 L/kg, 61 ± 13 min, and 111 (85–169) min, respectively. The corresponding parameters calculated after CRI were 13.5 ± 1.06 mL/min/kg, 0.993 ± 0.415 L/kg, 73 ± 27 min, and 49 (31–69) min. Ampicillin concentration decreased by 30% in the Ringer's lactate infusion solution mostly during the first hour after preparation of the solution. Constant rate infusion of Ringer's lactate solution during 8 h caused significant changes in ampicillin pharmacokinetics. The results suggested that special attention should be given to drug pharmacokinetics when co‐administered intravenously with electrolyte solutions.  相似文献   

16.
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 dss) 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.  相似文献   

17.
The objective of this study was to describe the pharmacokinetics (PK) of cytarabine (CA) after subcutaneous (SC) administration to dogs with meningoencephalomyelitis of unknown etiology (MUE). Twelve dogs received a single SC dose of CA at 50 mg/m2 as part of treatment of MUE. A sparse sampling technique was used to collect four blood samples from each dog from 0 to 360 min after administration. All dogs were concurrently receiving prednisone (0.5–2 mg kg?1day?1). Plasma CA concentrations were measured by HPLC, and pharmacokinetic parameters were estimated using nonlinear mixed‐effects modeling (NLME). Plasma drug concentrations ranged from 0.05 to 2.8 μg/ml. The population estimate (CV%) for elimination half‐life and Tmax of cytarabine in dogs was 1.09 (21.93) hr and 0.55 (51.03) hr, respectively. The volume of distribution per fraction absorbed was 976.31 (10.85%) ml/kg. Mean plasma concentration of CA for all dogs was above 1.0 μg/ml at the 30‐, 60‐, 90‐, and 120‐min time points. In this study, the pharmacokinetics of CA in dogs with MUE after a single 50 mg/m2 SC injection in dogs was similar to what has been previously reported in healthy beagles; there was moderate variability in the population estimates in this clinical population of dogs.  相似文献   

18.
OBJECTIVE: To determine the effectiveness and safety of 2 sedative-analgesic protocols to facilitate assisted ventilation in healthy dogs. ANIMALS: 12 healthy dogs. PROCEDURES: Dogs were randomly assigned to 2 groups. Mean dosages for protocol 1 were diazepam (0.5 mg/kg/h [n = 3 dogs]) or midazolam (0.5 mg/kg/h [3]), morphine (0.6 mg/kg/h [6]), and medetomidine (1.0 microg/kg/h [6]). Mean dosages for protocol 2 were diazepam (0.5 mg/kg/h [n = 3]) or midazolam (0.5 mg/kg/h [3]), fentanyl (18 microg/kg/h [6]), and propofol (2.5 mg/kg/h [6]). Each dog received the drugs for 24 consecutive hours. All dogs were mechanically ventilated with adjustments in minute volume to maintain normocapnia and normoxemia. Cardiorespiratory variables were recorded. A numeric comfort score was assigned hourly to assess efficacy. Mouth care, position change, and physiotherapy were performed every 6 hours. Urine output was measured every 4 hours. RESULTS: Use of both protocols maintained dogs within optimal comfort ranges > 85% of the time. The first dog in each group was excluded from the study. Significant decreases in heart rate, oxygen consumption, and oxygen extraction ratio were evident for protocol 1. Cardiac index values in ventilated dogs were lower than values reported for healthy unsedated dogs. Oxygen delivery, lactate concentration, and arterial base excess remained within reference ranges for both protocols. CONCLUSIONS AND CLINICAL RELEVANCE: Use of both protocols was effective for facilitating mechanical ventilation. A reduction in cardiac index was detected for both protocols as a result of bradycardia. However, oxygen delivery and global tissue perfusion were not negatively affected.  相似文献   

19.
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.  相似文献   

20.
The pharmacokinetics of cefepime, a new fourth generation cephalosporin with enhanced antibacterial activity, was examined in neonatal foals and adult dogs. Cefepime was administered intravenously (i.v.) at a dose of 14 mg/kg to five neonatal foals and six adult dogs. Blood samples were collected in both groups of animals and plasma cefepime concentrations measured by reverse-phase high-performance liquid chromatography (HPLC). Cefepime concentrations in both groups of animals were described by a two-compartment pharmacokinetic model with elimination half-lives of 1.65 and 1.09 h for the foal and dog, respectively. We tested whether or not pharmacokinetic parameters for cefepime could be scaled across species using principles of allometry. The parameters of elimination half-life (t(1/2)beta), apparent volume of distribution (VDarea), and systemic clearance (CL) were scaled linearly to body weight on a double logarithmic plot with allometric exponents for body weight of 0.26, 1.08 and 0.72, respectively. This study further determined doses for cefepime, a potentially useful antibiotic for neonatal foals and dogs, from the pharmacokinetic values. An i.v. dose of cefepime estimated from this study for treating sensitive bacteria was 11 mg/kg every 8 h for neonatal foals and 40 mg/kg every 6 h for dogs.  相似文献   

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