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R J Carapetis

Publications and source records attributed to R J Carapetis.

12 recordsLinked to original sources
PubMed1991

Uptake and elution of chlormethiazole, meperidine, and minaxolone in the hindquarters of sheep: implications for clearance calculations.

Mass balance principles were used to describe the uptake and elution of chlormethiazole, meperidine, and minaxolone in the hindquarters of sheep. Sheep received a right atrial infusion of either chlormethiazole (3.71 mg/min) or meperidine (2.70 mg/min) for 180 min, or minaxolone (0.37 mg/min) for 120 min. Paired arterial and inferior vena cava (draining the hindquarters) blood samples were taken during and after the infusion. The mean and SD (n = 4) of the time-averaged extraction ratios across the hindquarters (determined from the relevant arterio-venous area under blood concentration--time curves) were 0.12 (0.10), 0.36 (0.13), and 0.27 (0.05) for chlormethiazole, meperidine, and minaxolone, respectively. The rank order of the rate of uptake of the drugs into the hindquarters was the same as the rank order of their lipophilicity, and uptake still continued when both the arterial and inferior vena cava drug concentrations were essentially constant. For chlormethiazole, meperidine, and minaxolone, 48% (44), 4% (6), and 35% (17), respectively, of the drug taken into the hindquarters eluted from the hindquarters after the infusion. Drug uptake and retention in extravisceral tissues, represented here by the hindquarters, can result in the mean total body drug clearance being overestimated when determined by traditional systemic pharmacokinetic methods.

Anesthetics↗
PubMed1990

Physiological and biochemical consequences of electroimobilisation in conscious sheep.

An electroimmobilisation device has been developed to facilitate the automated shearing of sheep, but there is little information on its effects on the body. We have studied its effects on the cardiovascular system and on intermediary metabolism in sheep. Electroimmobilisation caused statistically significant increases in mean arterial pressure, heart rate, cardiac output, renal and hepatic and hindquarter glucose and lactate flux, organ and whole body oxygen flux, hindquarter blood flow and core temperature and decreases in arterial and posterior vena cava blood pH, renal and hepatic blood flow and PaCO2. Notably, no change occurred in PaO2. The metabolic changes demonstrated the capacity of sheep to respond to the increased muscular and cardiovascular work induced by electroimmobilisation. Pulmonary function was not compromised during electroimmobilisation as judged from blood gas changes, and the acid/base changes were rapidly reversed after electroimmobilisation. The recovery to control conditions for all perturbations generally took no longer than 30 min, consistent with a rapid and physiologically adequate reversal by the animal's homeostatic mechanisms.

Acid-Base Equilibrium↗
PubMed1989

Myocardial and cerebral drug concentrations and the mechanisms of death after fatal intravenous doses of lidocaine, bupivacaine, and ropivacaine in the sheep.

This paper reports the cardiovascular effects of intentionally toxic intravenous doses of lidocaine, bupivacaine, and ropivacaine and the mechanisms of death. Fatal doses of lidocaine, bupivacaine, and ropivacaine were established in sheep treated with successive daily dose increments of each drug. The mean fatal dose of lidocaine (+/- SD) was 1450 +/- 191 mg (30.8 +/- 5.8 mg/kg), that of bupivacaine was 156 +/- 31 mg (3.7 +/- 1.1 mg/kg), and that of ropivacaine was 325 +/- 108 mg (7.3 +/- 1.0 mg/kg); thus the ratio of fatal doses was approximately 9:1:2. In four out of four lidocaine-treated animals, respiratory depression with bradycardia and hypotension without arrhythmias were the causes of death. Three out of four bupivacaine-treated animals died after the sudden onset of ventricular tachycardia/fibrillation without hypoxia or acidosis; the fourth died in a similar manner to the lidocaine-treated animals. Three out of five animals given ropivacaine died in a manner resembling the fatal effects of lidocaine-treated animals, but unlike the lidocaine-treated animals, in all three sheep there were also periods of ventricular arrhythmias. The remaining two ropivacaine-treated sheep died as a result of the sudden onset of ventricular tachycardia/fibrillation. The mean percentages of the fatal dose found in the myocardium was 2.8 +/- 0.7 for lidocaine-treated animals, 3.3 +/- 0.9 for bupivacaine-treated animals, and 2.2 +/- 1.4 for ropivacaine-treated animals; the corresponding percentages in whole brain were, respectively, 0.71 +/- 0.01, 0.71 +/- 0.21, and 0.89 +/- 0.27.

Amides↗
PubMed1988

The use of mass balance principles to describe regional drug distribution and elimination.

Mass balance principles were used to derive a number of terms that are helpful in describing the rate and extent of regional drug uptake. Regional drug uptake was defined as the net movement of drug from the blood perfusing a region into the extravascular space of the region due to the distribution and/or elimination of the drug. By analogy with the traditional physiological definition of flux, net drug flux was defined as the difference in mass per unit time of drug respectively entering and leaving a region via the arterial and venous blood vessels. The time-integral of net drug flux, net drug mass, was defined as the mass of drug that has entered a region via the arterial blood vessels but has not left the region via the venous blood vessels. For regions in which no drug elimination occurs, the mean regional drug concentration was defined as the net drug mass divided by the mass of the region. When a number of criteria are satisfied, the net drug flux is approximately the rate of drug uptake and the net drug mass is approximately the extent of drug uptake. Several examples are given to demonstrate the broad range of applications of mass balance principles. First, the method was used to characterize the differences between drug distribution and elimination in a hypothetical region using drug concentrations simulated from compartmental models of either distribution alone or distribution with elimination. Second, the whole body distribution net flux was described during a constant rate infusion of iodohippurate (IOH) into a sheep from the difference between the whole body net flux and renal net flux of IOH. Third, the time course of the mean myocardial lignocaine (lidocaine) concentrations in a sheep after an intravenous bolus of lignocaine were described. The time course of the lignocaine-induced depression of myocardial contractility followed more closely the mean myocardial lignocaine concentrations than that of either the arterial or coronary sinus blood concentrations. It is concluded that the use of mass balance principles provides a simple, empirical, and physiologically based method for the determination of the rate and extent of both drug distribution and elimination in regions as simple as single organs or as complex as the whole body.

Lidocaine↗
PubMed1987

The effects of general anaesthesia on tocainide clearance in the sheep.

The haemodynamic effects and regional clearances of tocainide were investigated in sheep with chronic intravascular cannulae to measure blood flow through, and drug extraction by, lungs, kidneys, liver and gut. 2. Tocainide, at arterial blood concentrations in the therapeutic range, caused no haemodynamic effects and was significantly extracted only by the liver. 3. In the presence of general anaesthesia with halothane, the mean hepatic blood flow and tocainide extraction ratio were each reduced by approximately 25% so that the mean hepatic clearance and intrinsic clearance of tocainide each were reduced by approximately 50%. Thus arterial blood tocainide concentrations were increased by 50%. 4. While the clinical implications of this interaction are unclear because of insufficient information about the margin of safety of tocainide, the pharmacological implications are plain. Because general anaesthesia may alter the relationship between dose and blood drug concentrations, pharmacokinetic and pharmacodynamic data should not be interchanged between awake and anaesthetized subjects.

Anesthesia, General↗
PubMed1986

A sheep preparation for studying interactions between blood flow and drug disposition. VI: Effects of general or subarachnoid anaesthesia on blood flow and chlormethiazole disposition.

Blood flow through and chlormethiazole extraction ratios across lungs, liver, kidneys and gut were measured in awake unrestrained sheep (controls) and with the same animals anaesthetized with 1.5% halothane or whilst undergoing high thoracic subarachnoid blockade with amethocaine. In the control-drug studies, chlormethiazole infused to sub-sedative blood concentrations produced no significant changes in haemodynamics or in the kinetics of iodohippurate (renal and hepatic blood flows). Chlormethiazole was eliminated predominantly by the liver (mean extraction ratio and clearance, respectively, 0.90 and 1.3 litre min-1) and lungs (0.15; 0.6 litre min-1). Renal clearance was absent or negligible (greater than 0.1 litre min-1). Because of pulmonary clearance, mean total body clearance was derived from analysis of pulmonary arterial concentrations. Under general anaesthesia, there were significant reductions in mean cardiac output, hepatic and renal blood flow (to 54%, 63% and 43% of control); chlormethiazole mean hepatic extraction ratios and clearance were reduced, respectively, to 82% and 56% of control, and its pulmonary and renal clearances were abolished. With subarachnoid anaesthesia there were no significant changes in haemodynamics or in chlormethiazole extraction ratios or clearances.

Anesthesia, General↗
PubMed1986

A sheep preparation for studying interactions between blood flow and drug disposition. V: The effects of general and subarachnoid anaesthesia on blood flow and pethidine disposition.

Blood flow through and pethidine extraction ratios across lungs, liver, kidneys and the gastrointestinal tract were measured in awake unrestrained sheep (controls) and with the animals anaesthetized with 1.5% halothane or whilst undergoing high thoracic subarachnoid block with amethocaine. In the control studies, pethidine infused to several times the blood concentrations required for postoperative analgesia in man produced no significant changes in haemodynamics or in the kinetics of iodohippurate (renal and hepatic blood flow); pethidine hepatic extraction ratios were consistently greater than 0.97; renal extraction ratios ranged from negligible to 0.30; and there was negligible extraction across the lungs and the gastrointestinal tract. Under general anaesthesia there were significant reductions in mean cardiac output (46%), mean hepatic blood flow (46%), mean renal blood flow (55%), mean arterial pressure (30%) and mean iodohippurate clearance (17%); but mean arterial blood concentrations of pethidine were doubled, mean hepatic clearance of pethidine was reduced to 60% of control and renal clearance was virtually abolished. With subarachnoid anaesthesia there were no significant changes in haemodynamics or in pethidine or iodohippurate extraction ratios or clearances. Summed measured regional clearances accounted for only one- to two-thirds of the total body clearance of pethidine; the rest was by extravisceral clearance or high affinity tissue binding.

Anesthesia, General↗
PubMed1986

Hepatic and renal clearances of lidocaine in conscious and anesthetized sheep.

Sheep were implanted with cannulae to study blood flow through, and drug extraction by, the lungs, kidneys, liver, and gut. Lidocaine, infused to a steady state in conscious sheep, caused no significant changes in cardiac output or regional blood flow, and was cleared principally by the liver, where the extraction ratio usually exceeded 0.9, and by the kidneys, where the extraction ratio was 0.1-0.2. There was no detectable clearance by lungs or gut. Under general anesthesia with 1.5% halothane, the cardiac output and renal and hepatic blood flows were decreased to means of 77, 44, and 79% of mean control values, respectively, but hepatic and renal extraction ratios of lidocaine were not systematically altered, so that regional clearances of lidocaine were not significantly different from those in conscious animals. There was evidence that the total body clearance of lidocaine exceeded the sum of the directly measured regional clearances in both control and general anesthesia studies. These equivocal findings of the effects of general anesthesia on lidocaine clearance are at variance with unequivocal findings of reduced regional clearances of other drugs tested in this preparation.

Anesthesia, General↗
PubMed1985

A sheep preparation for studying interactions between blood flow and drug disposition. IV: The effects of general and spinal anaesthesia on blood flow and cefoxitin disposition.

Control measurements of blood flow through and cefoxitin extraction ratios across heart and lungs, liver, kidneys and gut were made under steady-state conditions in awake unrestrained sheep. The studies then were repeated with the same animals anaesthetized with 1.5% halothane or whilst undergoing high thoracic (to approximately T4) subarachnoid blockade with amethocaine. In the control-drug studies, it was shown that cefoxitin was cleared by the kidneys and that the cefoxitin infusion produced no significant changes in haemodynamics or in the kinetics of iodohippurate (the marker substance used for determining renal blood flow). Under general anaesthesia, there were significant reductions in renal blood flow (to 61% of the mean control value), in iodohippurate renal extraction ratio and clearance (to, respectively, 64 and 38% of the mean control values) and in cefoxitin renal extraction ratio and clearance (to, respectively, 48 and 23% of the mean control values). Under spinal anaesthesia there were no significant changes in haemodynamics or in cefoxitin or iodohippurate extraction ratios or clearances.

Anesthesia, General↗
PubMed1984

A sheep preparation for studying interactions between blood flow and drug disposition. II: Experimental applications.

A sheep preparation has been developed which allows systematic direct studies into the sites and rates of distribution, formation and elimination of both endogenous and exogenous substances and their metabolites. Examples of some experimental applications are presented which provide information not usually available using traditional methods. Substantial metabolism at sites not usually regarded as important (e.g. limbs, lungs) was shown both for exogenous substances (procainamide and chlormethiazole) and for an endogenous substance (choline). Studies on drug clearance by kidney (cefoxitin), liver (chlormethiazole, pethidine and the optical isomers of mepivacaine) and lung (chlormethiazole) demonstrate that simple first-order elimination should not routinely be assumed to occur, as multiple sites and pathways may be involved, and kinetics may be non-linear as a result of characteristics of both organ flow and organ function. It was also shown that large changes (up to three-fold) in arterial blood drug concentrations may occur because of exogenous (anaesthesia) and endogenous (gastric recycling) perturbations, and that simple compartmental kinetics should not be assumed for either the whole body or individual organs. This preparation may be used in conjunction with traditional pharmacokinetic methods to resolve complex problems relating to interactions between drugs and the body, to establish a data base for physiological models of drug disposition, and to gain practical insights for drug treatment in patients.

Anesthesia, General↗
PubMed1984

A sheep preparation for studying interactions between blood flow and drug disposition. III: Effects of general and spinal anaesthesia on regional blood flow and oxygen tensions.

In awake unrestrained sheep the infusions i.v. of five drugs (cefoxitin, pethidine, chlormethiazole, tocainide and lignocaine) with potentially flow-limited clearance were shown to have no significant haemodynamic effects of their own, nor to have any effects on arterial or venous oxygen tensions. Under general anaesthesia (1.5% end-tidal halothane), haemodynamic changes similar to those previously documented in man occurred. Cardiac output and hepatic blood flow were decreased to 70%, and renal blood flow to 50% of control values; heart rate was unchanged and mean arterial pressure decreased by an average of 10%. Hepatic and renal vein oxygen tensions were decreased significantly. Under spinal anaesthesia, apart from a 10% decrease in hepatic blood flow, there were no significant changes in any haemodynamic variables or in the arterial or in any of the venous oxygen tensions. The i.v. infusion of adequate volumes of saline at the time of blockade probably contributed to the maintenance of these indices at their baseline values.

Anesthesia, General↗