Pharmacokinetics of Prilocaine after Intravenous Administration in Volunteers: Enantioselectivity

Background: Prilocaine exists in two stereoisomeric configurations, the enantiomers s(+)- and R(-)-prilocaine. The drug is clinically used as the racemate. This study examined the pharmacokinetics of the enantiomers after intravenous administration of the racemate.

Methods: Ten healthy male volunteers received 200 mg racemic prilocaine as a 10-min intravenous infusion. Blood samples were collected for 8 h after the start of the infusion. Plasma concentrations were measured by stereoselective high-performance liquid chromatography (HPLC). Unbound fractions of the enantiomers in blank blood samples, spiked with racemic prilocaine, were determined using equilibrium dialysis.

Results: The unbound fraction of R(-)-prilocaine (mean +/- SD, 70% +/- 8%) was smaller (P < 0.05) than that of S(+)-prilocaine (73% +/- 5%). The total plasma clearance of R(-)-prilocaine (2.57 +/- 0.46 l/min) was larger (P < 0.0001) than that of S(+)-prilocaine (1.91 +/- 0.30 l/min). The steady-state volume of distribution of R(-)-prilocaine (279 +/- 94 l) did not differ from that of S(+)-prilocaine (291 +/- 93 l). The terminal half-life of R(-)-prilocaine (87 +/- 27 min) was shorter (P < 0.05) than that of S(+)-prilocaine (124 +/- 64 min), as was the mean residence time of R(-)-prilocaine (108 +/- 30 min) compared with S(+)-prilocaine (155 +/- 59 min; P < 0.005).     

Lack of Analgesic Activity of Morphine-6-glucuronide after Short-term Intravenous Administration in Healthy Volunteers

Background: The analgesic activity of morphine-6-glucuronide (M-6-G) is well recognized for its contribution to the effects of morphine and its possible use as an opioid analgesic with a wider therapeutic range than morphine. The present study attempted to quantify the relative contribution of M-6-G to analgesia observed after systemic administration of morphine.

Methods: In a placebo-controlled, sixfold crossover study in 20 healthy men, the effects of M-6-G were assessed at steady-state plasma concentrations of M-6-G identical to and two and three times higher than those measured after administration of morphine. Morphine and M-6-G were administered as an intravenous bolus followed by infusion over 4 h. Dosage A was M-6-G-bolus of 0.015 mg/kg plus infusion of 0.0072 mg [center dot] kg sup -1 [center dot] h sup -1. Dosage B was M-6-G-bolus of 0.029 mg/kg plus infusion of 0.014 mg [center dot] kg sup -1 [center dot] h sup -1. Dosage C was M-6-G-bolus of 0.044 mg/kg plus infusion of 0.022 mg [center dot] kg sup -1 [center dot] h sup -1. Dosage D was a morphine bolus of 0.14 mg/kg plus infusion of 0.05 mg [center dot] kg sup -1 [center dot] h sup -1 for 4 h. Dosage E was M-6-G combined with morphine (doses A + D). Dosage F was a placebo. The analgesic effects of M-6-G and morphine were measured before administration of the bolus and after 3.5 h using an experimental pain model based on pain-related cortical potentials and pain ratings after specific stimulation of the nasal nociceptor with short pulses of gaseous carbon dioxide.

Results: Morphine significantly reduced subjective and objective pain correlates compared with placebo. In contrast, M-6-G produced no statistically significant effects. The addition of M-6-G to morphine did not increase the effects of morphine. Morphine produced significantly more side effects than M-6-G.     

Concentration-Effect Relationships of Eltanolone Given as a Bolus Dose or Constant Rate Intravenous Infusion to Healthy Male Volunteers

Background: The primary purpose of this study was to evaluate concentration-effect relationships of the new steroid anesthetic eltanolone during recovery from a bolus dose and constant rate intravenous infusion in healthy male volunteers.

Methods: Ten subjects received a bolus dose of 0.75 mg/kg eltanolone over 20 s. A 2-h constant rate intravenous infusion of eltanolone was given to five subjects at a rate of 2 mg *symbol* kg sup -1 *symbol* h sup -1 and to another five subjects at a rate of 3.5 mg *symbol* kg sup -1 *symbol* h sup -1. Recovery performance was assessed as the time required to reach different end-points and by means of three different psychomotor tests.

Results: A low interindividual variability was found in the serum concentration of eltanolone at the pharmacodynamic end-points during recovery. The Cp50 value for "eye opening" was 382 micro gram/l (95% confidence interval, 285-489) after a bolus dose corresponding to a median time of 16 min (range 8-25). After eltanolone infusion, the Cp50 value for "eye opening" was 507 micro gram/l (95% confidence interval, 425-605) and the corresponding median time was 21 min (range 8-25) in the low-dose group and 49 min (range 31-66) in the high-dose group. The Cp50 values at the same effect end-points in the bolus group were less than those in the infusion groups, probably because of insufficient equilibration time between serum and the effect compartment.     

Pharmacokinetics and Arteriovenous Differences in Clevidipine Concentration following a Short- and a Long-term Intravenous Infusion in Healthy Volunteers

Background: Clevidipine is an ultra-short-acting calcium antagonist developed for reduction and control of blood pressure during cardiac surgery. The objectives of the current study were to determine the pharmacokinetics of clevidipine after 20-min and 24-h intravenous infusions, and to determine the relation between the arterial and venous concentrations and the hemodynamic responses to clevidipine in healthy volunteers.

Methods: Four volunteers received clevidipine for 20 min, and eight subjects were administered clevidipine intravenously for 24 h at two different dose rates. Arterial and venous blood samples were drawn for pharmacokinetic evaluation, and blood pressure and heart rate were recorded.

Results: A triexponential disposition model described the pharmacokinetics of clevidipine. The mean arterial blood clearance of clevidipine was 0.069 l [middle dot] kg-1 [middle dot] min-1 and the mean volume of distribution at steady state was 0.19 l/kg. The duration of the infusion had negligible effect on the pharmacokinetic parameters, and the context-sensitive half-time for clevidipine, simulated from the mean pharmacokinetic parameters derived after 24 h infusion at the highest dose, was less than 1 min. The arterial blood levels reached steady state within 2 min of the start of infusion and were about twice as high as those in the venous blood at steady state. The peak response preceded the peak venous concentration and was slightly delayed from the peak arterial blood concentration.     

体外循环手术中从中心静脉推注与滴注鱼精蛋白的比较

在体外循环手术中,作者通过比较从中心静脉推注与滴注鱼精蛋白(PRTM),发现均可引起血管扩张、血压下降,但推注法血压下降值明显大于滴注法,且术后24h出血量推注法也明显多于滴注法。故认为滴注法优于推注法。     

Propofol Alters the Pharmacokinetics of Alfentanil in Healthy Male Volunteers

Background: The influence of propofol on the pharmacokinetics of alfentanil is poorly understood. The authors therefore studied the effect of a pseudo-steady state concentration of propofol on the pharmacokinetics of alfentanil.

Methods: The pharmacokinetics of alfentanil was studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While breathing 30% O2 in air, 12.5 [mu]g/kg intravenous alfentanil was given in 2 min, followed by 25 [mu]g [middle dot] kg-1 [middle dot] h-1 for 58 min (sessions A and B). During session B, a target controlled infusion of propofol (target concentration, 1.5 [mu]g/ml) was given from 10 min before the start until 6 h after termination of the alfentanil infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the plasma alfentanil concentration were collected until 6 h after termination of the alfentanil infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of propofol and mean arterial pressure were constructed.

Results: A three-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of alfentanil. Propofol decreased the elimination clearance of alfentanil by 15%, rapid distribution clearance by 68%, slow distribution clearance by 51%, and lag time by 62%. Mean arterial pressure and systemic vascular resistance were significantly lower in the presence of propofol. Scaling the pharmacokinetic parameters to the mean arterial pressure instead of propofol improved the model.     

Pharmacokinetics and Pharmacodynamics of Propofol Microemulsion and Lipid Emulsion after an Intravenous Bolus and Variable Rate Infusion

Background: The aim of this trial was to evaluate the induction and recovery characteristics of microemulsion propofol (Aquafol; Daewon Pharmaceutical Co., Ltd., Seoul, Korea). Pharmacokinetics, pharmacodynamics, and safety profile were investigated. Lipid emulsion propofol (Diprivan(R); AstraZeneca, London, United Kingdom) was used as a comparator.

Methods: Thirty-one healthy volunteers aged 20-79 yr were given an intravenous bolus of propofol 2 mg/kg, followed by variable rate infusion for 60 min. Each volunteer was studied twice with different formulations at an interval of 1 week. Arterial concentrations of propofol were measured, and Bispectral Index was used as a surrogate measure of propofol effect. The induction and recovery characteristics including bioequivalence were evaluated by noncompartmental analysis. The pharmacokinetics and pharmacodynamics were investigated using a population approach with mixed effects modeling. The rate, severity, and causal relation of adverse events were analyzed.

Results: Both formulations were bioequivalent. The observed time to peak effect after a bolus of both formulations was 1.5 min. Plasma concentration of propofol at loss of consciousness, time to loss of consciousness after a bolus, and time to recovery of consciousness after discontinuation of infusion did not show significant differences. The population pharmacokinetics and pharmacodynamics revealed a variety of differences between two formulations. Aquafol showed similar safety profile to Diprivan(R).     

Pharmacokinetic Modeling of M6G Formation after Oral Administration of Morphine in Healthy Volunteers

Background: Morphine is metabolized to two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide (M6G). Under the conditions of long-term oral morphine administration, the accumulation of M6G may contribute to the analgesic effects, but it may also cause respiratory depression.

Methods: Five healthy male volunteers (ages 25-34 yr) received 90 mg MST (morphine sulfate 5H2 O sustained-released tablet, equivalent to 67.8 mg oral morphine). Multiple plasma and urine samples were taken for as long as 14 and 36 h, respectively. Individual pharmacokinetics after intravenous administration of morphine and M6G were available from a previous investigation. A new model that considers the M6G-plasma profile as a sum of the input from the first-pass metabolism of morphine and the input from systemically available morphine was applied to the plasma concentration versus time curves of M6G. The concentrations of M6G at the effect site after long-term morphine administration were simulated.

Results: The fraction of morphine absorbed from the gut was 82 +/- 14%. Of this, 42 +/- 8% passed through the liver, resulting in an oral bioavailability of morphine of 34 +/- 9%. Of the total amount of M6G, 71 +/- 7% was formed during the first-pass metabolism, and 29 +/- 7% was formed by metabolism of systemic morphine. After 36 h, the amounts of M6G and morphine excreted in the urine were 92 +/- 17% and 9 +/- 3%, respectively. Simulation of effect-site concentrations of M6G indicated that after multiple oral dosing of morphine in patients with normal liver and renal function, M6G might reach concentrations two times greater than that of morphine.     

Placental Transfer and Pharmacokinetics of Atropine after a Single Maternal Intravenous and Intramuscular Administration

The placental transfer and pharmacokinetics of atropine were studied in 44 healthy parturients undergoing caesarean section. The concentrations in the plasma were determined by a new radioimmunoassay after intravenous (n = 32) or after intramuscular (n = 12) administration of 0.01 mg/kg of atropine. A fast placental transfer with apparent foetal uptake of the drug was found after intravenous injection. There was also a difference in the umbilical vein and artery concentrations after intramuscular administration. The maternal pharmacokinetics of i.v. atropine obeyed a two-compartment open model with a fast distribution phase (mean tα_1/2 = 1.02 min) and quite fast elimination (t_1/2 = 2.56 h). The total apparent volume of distribution was 1.0 1/kg and the total plasma clearance 6.36 ml/min/kg. The mean peak maternal plasma levels after i.m. atropine administration were found at 1.59 h and the mean calculated half-life of elimination was then 2.1 h. No atropine was found in the amniotic fluid.     

Pharmacokinetics of Miocamycin Following Intravenous Administration to Cattle

The plasma pharmacokinetics for a single intravenous dose (10 mg/kg body weight) of miocamycin (a 16‐membered macrolide drug) was investigated in Holando Argentino cattle (n = 5). Blood drug concentrations were determined by a microbiological method and data were best‐fitted to a two‐compartment open model. The pharmacokinetic profile consisted of a short distribution phase (t_1/2α = 7.41 ± 0.53 min), followed by an extended terminal elimination phase (t_1/2β = 2.49 ± 0.23 h). The volume of distribution at steady‐state was large (2.13 ± 0.17 l/kg), suggesting extensive tissue distribution, the clearance value was 0.60 ± 0.03 l/h.     

Input Characteristics and Bioavailability after Administration of Immediate and a New Extended-release Formulation of Hydromorphone in Healthy Volunteers

Background: To compare the pharmacokinetics of intravenous, oral immediate-release (IR), and oral extended-release (OROS(R)) formulations of hydromorphone.

Methods: In this randomized, six-session, crossover-design study, 12 subjects received hydromorphone 8-mg intravenous, 8-mg IR oral, and 8-, 16-, and 32-mg OROS(R) formulations or placebo orally followed by plasma sampling for hydromorphone determination. Pharmacokinetic analysis was performed using NONMEM. Using the disposition of hydromorphone from the intravenous administration, deconvolution was used to estimate the input rate function (release rate from the gut to the blood) for the IR and OROS(R) formulations. A linear spline was used to describe the drug input rate function.

Results: The deconvolution using linear splines described the in vivo release characteristics of both the IR and OROS(R) formulations. The mean absolute bioavailability for the 8-mg OROS(R) formulation was significantly larger (P = 0.025) than for the 8-mg IR formulation: 0.24 (SD 0.059) versus 0.19 (SD 0.054), respectively. The bioavailability was the same for the three doses of the OROS(R) formulation. Predicted degree of fluctuation of plasma concentrations would be expected to be 130% and 39% for the IR and OROS(R) 8-mg doses, respectively.     

Remifentanil Versus Alfentanil: Comparative Pharmacokinetics and Pharmacodynamics in Healthy Adult Male Volunteers

Background: Remifentanil is an esterase-metabolized opioid with a rapid clearance. The aim of this study was to contrast the pharmacokinetics and pharmacodynamics of remifentanil and alfentanil in healthy, adult male volunteers.

Methods: Ten volunteers received infusions of remifentanil and alfentanil on separate study sessions using a randomized, open-label crossover design. Arterial blood samples were analyzed to determine drug blood concentrations. The electroencephalogram was employed as the measure of drug effect. The pharmacokinetics were characterized using a moment analysis, a nonlinear mixed effects model (NONMEM) population analysis, and context-sensitive half-time computer simulations. After processing the raw electroencephalogram to obtain the spectral edge parameter, the pharmacodynamics were characterized using an effect compartment, inhibitory maximum effect model.

Results: Pharmacokinetically, the two drugs are similar in terms of steady-state distribution volume (VDss), but remifentanil's central clearance (CLc) is substantially greater. The NONMEM analysis population pharmacokinetic parameters for remifentanil include a CLc of 2.9 l *symbol* min sup -1, a VDss of 21.81, and a terminal half-life of 35.1 min. Corresponding NONMEM parameters for alfentanil are 0.36 l *symbol* min sup -1, 34.11, and 94.5 min. Pharmacodynamically, the drugs are similar in terms of the time required for equilibration between blood and the effect-site concentrations, as evidenced by a T12 Ke0 for remifentanil of 1.6 min and 0.96 min for alfentanil. However, remifentanil is 19 times more potent than alfentanil, with an effective concentration for 50% maximal effect of 19.9 ng *symbol* ml sup -1 versus 375.9 ng *symbol* ml sup -1 for alfentanil.     

Pharmacokinetics of Rapacuronium in Infants and Children with Intravenous and Intramuscular Administration

Background: A nondepolarizing muscle relaxant with an onset and offset profile similar to succinylcholine is desirable for pediatric anesthesia. The onset and offset of rapacuronium are rapid in children. In the current study, the authors determined its pharmacokinetic characteristics in children. In addition to administering rapacuronium by the usual intravenous route, the authors also gave rapacuronium intramuscularly to determine uptake characteristics and bioavailability.

Methods: Forty unpremedicated patients aged 2 months to 3 yr were anesthetized with halothane, 0.82-1.0% end-tidal concentration. When anesthetic conditions were stable, rapacuronium was injected either into a peripheral vein (2 mg/kg for infants, 3 mg/kg for children) or a deltoid muscle (2.8 mg/kg for infants, 4.8 mg/kg for children). Four venous plasma samples were obtained from each subject 2-240 min after rapacuronium administration. A mixed-effects population pharmacokinetic analysis was applied to these values to determine bioavailability, absorption rate constant, and time to peak plasma concentration with intramuscular administration.

Results: Plasma clearance was 4.77 ml [middle dot] kg-1 [middle dot] min-1 + 8.48 ml/min. Intramuscular bioavailability averaged 56%. Absorption from the intramuscular depot had two rate constants: 0.0491 min-1 (72.4% of absorbed drug) and 0.0110 min-1 (27.6% of the absorbed drug). Simulation indicated that plasma concentration peaks 4.0 and 5.0 min after intramuscular rapacuronium in infants and children, respectively, and that, at 30 min, less than 25% of the administered dose remains to be absorbed from the intramuscular depot.     

The Pharmacokinetics and Steady State Pharmacodynamics of Mivacurium in Children

Background: The authors previously showed that children require larger infusion rates of mivacurium than adults to maintain target twitch depression. Here, they determined whether there are differences between children and adults in mivacurium's pharmacokinetic and pharmacodynamic properties.

Methods: Twenty-seven patients aged 1-58 yr were anesthetized with nitrous oxide and isoflurane. Cholinesterase activity and adductor pollicis twitch tension in response to train-of-four stimuli were measured. Mivacurium was infused, targeting 90% twitch depression. When twitch was stably depressed 85%-95% for 10 min with no change in infusion rate for 15 min, plasma was sampled to determine concentrations of mivacurium's stereoisomers. Clearance of the trans-trans (Cltrans-trans) and cis-trans (Clcis-trans) isomers was determined as the mivacurium infusion rate (adjusted for isomer composition) divided by the concentration of that isomer. Using the Hill equation, assuming equipotency of the trans-trans and cis-trans isomers, and ignoring the contribution of the nonpotent cis-cis isomer, the authors estimated the steady state plasma concentration yielding 90% twitch depression, C90. The effect of age on cholinesterase activity, the infusion rate depressing twitch tension by 90% (IR90), C90, Cltrans-trans, and Clcis-trans was determined using linear regression.

Results: Cholinesterase activity, IR90, and C90 did not vary with age. Both Cltrans-trans (r2 = 0.19, P = 0.01) and Cl sub cis-trans (r2 = 0.19, P = 0.02) decreased with age.     

Pharmacokinetics Anesthesiologists, and Pharmacodynamics of Remifentanil in Persons with Renal Failure Compared with Healthy Volunteers

Background: Remifentanil is an opioid analgesic for use in anesthesia. An ester linkage renders it susceptible to rapid metabolism by blood and tissue esterases. Thus it was hypothesized that remifentanil elimination would be independent of renal function. Because its principal metabolite (GR90291) is eliminated renally, it would depend on renal function. This study was designed to evaluate the pharmacokinetics and pharmacodynamics of remifentanil and its metabolite in persons with and without renal failure.

Methods: Two groups of volunteers received two-stage infusions of remifentanil: low dose with 0.0125 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 1 h followed by 0.025 micro gram kg sup -1 [center dot] min sup -1 for 3 h; and high dose with 0.025 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 1 h followed by 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 3 h. Blood samples were collected for analysis of remifentanil and GR90291 concentrations. The pharmacokinetics of remifentanil were fit using a one-compartment pharmacokinetic model. Remifentanil's effect was determined intermittently using minute ventilation during a hypercapnic (7.5% CO2) challenge.

Results: Fifteen patients with renal failure and eight control participants were enrolled. The clearance and volume of distribution of remifentanil were not different between those with renal failure and the controls. Patients with renal failure showed a marked reduction in the elimination of GR90291; the half-life of the metabolite increased from 1.5 h in the controls to more than 26 h in patients with renal failure. The steady-state concentration of GR90291 is likely to be more than 25 times higher in persons with renal failure. There were no obvious differences in opioid effects on minute ventilation in the controls and in patients with renal failure.     

Systemic Absorption and Block after Epidural Injection of Ropivacaine in Healthy Volunteers

Background: For local anesthetics, the process of removal from the site of administration influences the duration of anesthesia and the risk for systemic toxicity to develop. The systemic absorption of epidural ropivacaine and the time profile of sensory and motor block were studied in healthy volunteers.

Methods: Nine persons simultaneously received 150 mg ropivacaine hydrochloride (7.5 mg/ml) epidurally and 40 mg deuterium-labeled (sup 2 H sub 3)ropivacaine hydrochloride (0.25 mg/ml) intravenously. Peripheral arterial and venous plasma samples were collected, and assessments of sensory and motor block were made.

Results: The arterial plasma concentrations increased faster than the venous concentrations, with 50% higher maximum concentrations after both intravenous and epidural administration. The absorption was biphasic. A correlation was seen between the duration of sensory block and the slower absorption half-life; that is, the longer the half-life, the longer the duration. The extent of spread varied among the volunteers, with the median upper block level not exceeding T12. The motor block (Bromage score 1) was of slower onset (median, 0.4 h) and of shorter duration (median, 4.1 h) than the sensory block (onset, 0.2 h; duration, 6.5 h at L2 medians).     

Transplacental Passage of Ketamine after Intravenous Administration

This study was designed to measure how fast and at what concentrations ketamine would enter the foeto-placental circulation, when administered intravenously to 10 healthy mothers immediately before forceps delivery, which was indicated by a delayed second stage of labour. It is shown that ketamine very rapidly passes the placenta, and that ketamine levels in cord blood exceed the levels in the maternal venous blood as early as 1 min 37 s after the injection. The ketamine levels in cord blood reach a maximum in the period 1 min 37 s to 2 min 5 s after the injection. Later they show a tendency to decline. A short-lasting, marked elevation of blood pressure was produced by the ketamine anaesthesia. Two of the newborn showed low Apgar scores at 1 min. In one of them this was probably attributable to the anaesthesia.     

The Influence of Method of Administration and Covariates on the Pharmacokinetics of Propofol in Adult Volunteers

Background: Unresolved issues with propofol include whether the pharmacokinetics are linear with dose, are influenced by method of administration (bolus vs. infusion), or are influenced by age. Recently, a new formulation of propofol emulsion, containing disodium edetate (EDTA), was introduced in the United States. Addition of EDTA was found by the manufacturer to significantly reduce bacterial growth. This study investigated the influences of method of administration, infusion rate, patient covariates, and EDTA on the pharmacokinetics of propofol.

Methods: Twenty-four healthy volunteers aged 26-81 yr were given a bolus dose of propofol, followed 1 h later by a 60-min infusion. Each volunteer was randomly assigned to an infusion rate of 25, 50, 100, or 200 micro gram [center dot] kg-1 [center dot] min-1. Each volunteer was studied twice under otherwise identical circumstances: once receiving propofol without EDTA and once receiving propofol with EDTA. The influence of the method of administration and of the volunteer covariates was explored by fitting a three-compartment mamillary model to the data. The influence of EDTA was investigated by direct comparison of the measured concentrations in both sessions.

Results: The concentrations of propofol with and without EDTA were not significantly different. The concentration measurements after the bolus dose were significantly underpredicted by the parameters obtained just from the infusion data. The kinetics of propofol were linear within the infusion range of 25-200 micro gram [center dot] kg-1 [center dot] min-1. Age was a significant covariate for Volume2 and Clearance2, as were weight, height, and lean body mass for the metabolic clearance.     

Influence of Escherichia coli Endotoxin‐Induced Endotoxaemia on the Pharmacokinetics of Enrofloxacin after Intravenous Administration in Rabbits

The main goal of present study was to determine the effects of an Escherichia coli endotoxin‐induced endotoxaemic status on disposition of enrofloxacin after a single intravenous dose (5 mg/kg) in rabbits. Septic shock was induced by the i.v. bolus administration at a single dose of E. coli lipopolysaccharide. Six adult New Zealand White rabbits were used. Concentrations of drug in plasma were determined by HPLC. The plasma pharmacokinetic values for enrofloxacin were best represented using a two‐compartment open model. Total plasma clearance (Cl_T) decreased from 2.11 (l/h/kg) in healthy animals to 1.50 (l/h/kg) in rabbits with septic shock, which is related to an increase in the AUC_0→∞. In endotoxaemic rabbits, volume of distribution at steady state (V_dss = 3.61 l/kg) was significantly lower (P < 0.05) than in healthy animals (V_dss = 4.97 l/kg). However, the elimination half‐life of enrofloxacin was not affected by lipopolysaccharide administration.