William B. Runciman

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 timeintegral 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.

The uptake and elution of lignocaine and procainamide in the hindquarters of the sheep described using mass balance principles.

Mass balance principles were used to describe the uptake and elution of lignocaine (lidocaine) and procainamide in the hindquarters of the sheep. Each of four sheep received a right atrial infusion of either lignocaine · HCl (2.7 mg/min) or procainamide · HCl (5.5mg/min) for 180 min. Paired arterial and inferior vena cava (draining the hindquarters) blood samples were taken at 20-min intervals during the infusion and for 180 min after the infusion. Lignocaine and procainamide mean total body clearances were 2.9 L/min (SD 1.1) and 1.3 L/min (SD 0.2), respectively. An index of the uptake and elution of these drugs in the hindquarters was estimated from the net drug mass per unit hindquarter blood flow;indirect evidence suggested that hindquarter blood flow was constant. All the net mass/flow of procainamide that was taken into the hindquarters during the infusion also eluted after the infusion, demonstrating reversible distribution into the tissues. However, uptake of procainamide was still occurring when blood concentrations were constant, indicating that the concentrations of procainamide in the hindquarters were not in equilibrium with the inferior vena cava concentrations. Lignocaine did not reach constant blood concentrations during the infusion and showed no tendency to reach arteriovenous equilibration; an arteriovenous difference of 22%(SD5%) across the hindquarters was measured during the last 60 min of the infusion. By 180 min after the lignocaine infusions, 79% (SD 8%) of the lignocaine net mass/flow had not eluted from the hindquarters when arterial and venous lignocaine concentrations were not significantly different. This drug could remain uneluted due to metabolism and/or avid tissue binding, and presents difficulties in the interpretation of pharmacokinetic data whether based on arterial or venous blood sampling.

The in vitro uptake and metabolism of lignocaine, procainamide and pethidine by tissues of the hindquarters of sheep

1. In vitro studies using tissue slices or tissue homogenates of liver, skeletal muscle, fat skin and blood were conducted to determine whether the uptake of procainamide, lignocaine and pethidine into the hindquarters of sheep was due to distribution or metabolism. Both homogenates and slice preparations of liver showed significant metabolism or uptake, confirming the viability of the preparations. 2. None of the drugs was metabolized in blood and there was minimal uptake of the drugs into the skin. 3. There was metabolism of pethidine in skeletal muscle and substantial uptake of pethidine into fat, indicating that the rapid rate of uptake and prolonged elution of pethidine in the hindquarters was due to both distribution and metabolism. 4. No metabolism of lignocaine in muscle was found, but there was substantial uptake into fat, indicating that the rapid rate of uptake and prolonged elution of lignocaine in the hindquarters was due to its distribution into fat. 5. There was negligible uptake of procainamide into either muscle or fat, presumably due to its relatively low lipophilicity.

The in vivo blood, fat and muscle concentrations of lignocaine and bupivacaine in the hindquarters of sheep

1. A method was developed for sampling muscle and fat from the hindquarters of sheep undergoing spinal anaesthesia. The method was used to measure the concentrations of lignocaine and bupivacaine in the blood, muscle and fat of the hindquarters of sheep during and after 180 min constant-rate infusions of the drugs. 2. For both drugs the muscle drug concentrations were a relatively constant ratio of the simultaneous arterial blood drug concentrations during and after the infusion. 3. There was uptake of both lignocaine and bupivacaine into subcutaneous fat during the infusions. At the end of the infusion the ratio of the fat: arterial blood drug concentrations were 1.54 (SD = 0.57, n = 4) and 3.1 (SD = 1.4, n = 4) for lignocaine and bupivacaine, respectively. 4. The drug concentrations in fat declined relatively slowly after the infusion. The ratio of the fat: arterial blood drug concentrations 180 min after the end of the infusion was 21.5 (SD 4.0, n = 3) and for lignocaine, and 120 min after the end of the infusion was 9.54 (SD 5.2, n = 3) for bupivacaine. 5. It was concluded that the concentrations of lignocaine and bupivacaine in muscle were essentially in equilibrium with the arterial concentrations during and after the infusion. However, the concentrations of lignocaine and bupivacaine in fat were not in equilibrium with the arterial concentrations in the post-infusion period.

The influence of drug sorption on pharmacokinetic studies of chlormethiazole and lignocaine

The influence of drug sorption on the measurement of dose and blood concentrations during pharmacokinetic studies of chlormethiazole and lignocaine in a chronically catheterized sheep preparation has been examined. There was no sorption to soda glass tubes, borosilicate glass volumetric flasks or soda glass microlitre syringes but minor sorption to polypropylene syringes, polypropylene pipette tips and rubber bottle stoppers after 240 min contact. During infusions through administration sets including either polyvinyl chloride or polyethylene catheters, no significant loss of lignocaine occurred, but only 41ṁ7–63ṁ9% of the chlormethiazole dose was delivered. No significant decreases in either drug occurred from blood sampled through an intravascular catheter and stopcock system. There was negligible degradation of the samples over 4 h. Sorption of chlormethiazole or lignocaine to the laboratory equipment used was not a significant source of error but polyvinyl chloride infusion catheters could result in significant reductions in chlormethiazole dose.

Failure of the Kety-Schmidt nitrous oxide method for determination of myocardial blood flow.

1. The reliability of the Kety‐Schmidt nitrous oxide (N2O) blood–tissue equilibration method was examined in 50 studies of myocardial blood flow in seven conscious, unrestrained sheep using a newly developed carefully validated gas chromatographic assay for N2O.

FAILURE OF THE NITROUS OXIDE TISSUE EQUILIBRATION METHOD FOR THE DETERMINATION OF BRAIN AND MYOCARDIAL BLOOD FLOW UNDER CONTROLLED CONDITIONS

1. Two adult merino ewes were prepared with intravascular cannule for sampling aortic root blood, sagittal sinus blood and coronary sinus blood.

An animal model of systemic carnitine deficiency produced by haemodialysis of sheep

1. Sheep, which had previously been surgically prepared with cannulae in various vessels to monitor substrate and metabolite exchanges across all the major organs, were connected to a haemodialysis machine and their blood was dialysed at an average rate of 6.23 ml/min/kg body weight. 2. Dialysis for 4 hr reduced the blood free carnitine concentrations to approx. 50% of the initial values and the concentrations returned to the initial values after 18 hr recovery. 3. Carnitine balance studies showed that approx. twice the amount of carnitine lost from the blood during dialysis passed into the dialysate indicating that carnitine was also lost from the extracellular fluid. 4. The average blood concentration of short-chain acylcarnitines did not vary significantly during dialysis or during the recovery phase. However, an output of short-chain acylcarnitines by the liver at 3 and 18 hr recovery and an uptake by the hind-body at 18 hr recovery was observed. 5. These results suggest that haemodialysis of sheep provides a useful model of systemic carnitine deficiency and suggest that treatment with acetylcarnitine or propionylcarnitine could be an efficient means of supplying carnitine in carnitine replacement therapy.

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.