David Lalka

Free Drug Concentration Monitoring in Clinical Practice

SummaryRecent advances in techniques to determine free drug concentrations have lead to a substantial increase in the monitoring of this parameter in clinical practice. The majority of drug binding to macromolecules in serum can be accounted for by association with albumin and α1-acid glycoprotein. Albumin is the primary binding protein for acidic drugs, while binding to α1-acid glycoprotein is more commonly observed with basic lipophilic agents. Alterations in the concentrations of either of these macromolecules can result in significant changes in free fraction. Diseases such as cirrhosis, nephrotic syndrome and malnourishment can result in hypoalbuminaemia. Burn injury, cancer, chronic pain syndrome, myocardial infarction, inflammatory diseases and trauma are all associated with elevations in the concentration of α1-acid glycoprotein. Treatment with a number of drugs has also been shown to increase α1-acid glycoprotein serum concentrations.A wide variety of biological fluids have been examined for their ability to provide an estimation of free drug concentration at receptor sites. The most useful fluid for estimating free drug concentrations appears to be plasma or serum, with subsequent treatment of the sample to separate free and bound drug by an appropriate technique. The two most widely used methods are equilibrium dialysis and ultrafiltration. Of these two, ultraflltration has the greatest utility clinically because it is rapid and relatively simple. The major difficulty associated with this method involves the binding of drug to the ultrafilters, but significant progress has been made in solving this problem.Several authors have enat]dorsed the routine use of free drug concentration monitoring. Data examining the clinical usefulness of free drug concentration monitoring for phenytoin, carbamazepine, valproic acid, disopyramide and lignocaine (lidocaine) are reviewed. While available evidence suggests that free concentrations may correlate with clinical effects better than total drug concentrations, there are insufficient data to justify the recommendation of the routine use of free drug concentration monitoring for any of these agents at present.

Food, splanchnic blood flow, and bioavailability of drugs subject to first-pass metabolism.

There has been considerable interest in the past fifteen years in determining the influence of food and diet on gastrointestinal drug absorption. Welling21 has recently presented a comprehensive and critical review of these efforts. In general, food reduces the absorption rate of drugs from the gastrointestinal tract but in most instances has little influence on the extent of absorption. Such an effect is clinically significant for sedative‐hypnotics and for other drugs where a prompt response is desired but is probably of little concern in most other cases. On the other hand, food has been found to substantially reduce the extent of absorption of certain drugs, including many antibiotics. This type of food effect often occurs with drugs with poor permeability characteristics that are incompletely absorbed even by fasting patients. Continual administration of such drugs with meals would result in lower steady‐state drug concentrations in plasma than would be found were the drug to be given under fasting conditions.

Effect of food on hepatic blood flow: Implications in the “food effect” phenomenon

It has been suggested that alteration in the apparent oral bioavailability of propranolol taken with food may be due to a transient increase in QH. To investigate this hypothesis more closely, the time course of effect of a high‐protein meal on QH was examined with the model compound ICG. Forty minutes postprandial, the mean increase in estimated QH was 69% above the control. QH was still elevated a mean of 36% at 100 min but by 280 min had decreased to a value that did not differ from control. Computer simulations were performed to predict the magnitude of change in the apparent oral bioavailability of propranolol that would be expected based on the observed QH changes. These simulations suggest that simple changes in QH alone cannot account for the increase in apparent oral bioavailability when propranolol is taken with food.

Factors influencing serum protein binding of lidocaine in humans

Several factors that may affect protein binding of lidocaine in human serum were studied in normal volunteers. Evidence was obtained for the presence of two classes of lidocaine binding sites with strikingly different affinity constants (k) and capacities (nP); k1 = 1.3 × 105 M-1 n1P1 = 1.7 × 10-5 M, and k2 = 6.4 × 101 M-1. n2P2 = 6.9 × 10-3 M. The low affinity binding sites are probably on serum albumin, whereas the high affinity site may be located on α1 acid glycoprotein. At a lidocaine serum concentration of approximately 1.4 μg/ml, it was observed that acidosis (pH 7.4 → 7.2) caused lidocaine-free fraction to increase from 0.29 to 0.36 (p < 0.01) and that the addition of the lidocaine metabolites 3-hydroxylidocaine, 4-hydroxylidocaine, monoethylglycinexylidide, and glycinexylidide had no effect on the binding of lidocaine. Bupivacaine, disopyramide, and quinidine (in concentrations that are observed clinically) caused a significant increase (p < 0.01) in the free fraction of lidocaine in serum (23%, 21%, and 34%, respectively). Interestingly, N-depropyl disopyramide, dihydroquinidine, procainamide, N-acetyl procainamide, and propranolol had no effect on lidocaine binding.

Effect of cimetidine on the pharmacokinetics and pharmacodynamics of quinidine.

The influence of cimetidine (1.2 g/day for 7 days) on the disposition and pharmacodynamic effects of a single oral dose of quinidine was studied in 6 normal volunteers. Cimetidine reduced the mean apparent oral clearance of quinidine (+/- standard error of the mean) from 25.5 +/- 2.7 to 16.2 +/- 1.4 liters/h (p less than 0.05). This was reflected in a 55% (range 30 to 109) increase in the mean half-life from 5.8 +/- 0.2 to 9.0 +/- 0.6 hours (p less than 0.05). Peak quinidine plasma concentrations and times to peak were also increased (p less than 0.05). Plasma protein binding and urinary excretion of quinidine were unchanged by cimetidine treatment. Alterations in the pharmacokinetic variables of quinidine were mirrored in simultaneously measured electrocardiographic parameters. Changes in Q-T, rate-corrected Q-T, QRS, and R-R intervals after a single oral dose of quinidine sulfate (400 mg) were significant. Treatment with cimetidine potentiated these pharmacodynamic changes, but failed to achieve significant differences from quinidine alone. Thus, cimetidine impairs the elimination of oral quinidine in normal volunteers. This interaction may lead to quinidine toxicity in patients in whom cimetidine is concomitantly administered.

Pulmonary Disease and Drug Kinetics

SummaryA number of examples of altered drug disposition in patients with respiratory disease have been reported. These reports have been analysed in terms of absorption, distribution and elimination. The changes have been examined mechanistically in light of the pathophysiology of respiratory disease and the known influence of these physiological parameters on drug disposition. Our analysis has included in vivo and in vitro data from laboratory animals in addition to appropriate data from humans.Acute hypoxaemia appears to decrease intrinsic hepatic clearance while chronic hypoxia appears to increase intrinsic clearance. The free fraction of some bases is decreased in plasma taken from patients with chronic hypoxaemia and this change can interact with changes in intrinsic metabolic activity. Blood gas disturbances also can affect drug disposition by decreasing hepatic and renal perfusion.Cor pulmonale has not been linked to altered drug disposition, except in the case of theophylline. However, this pathophysiological condition may be equivalent to congestive cardiac failure through diminished hepatic and renal perfusion.The marked reduction (approximately 50%) in theophylline clearance documented in some asthmatic patients may reflect protein binding changes, a paradoxical response of metabolic pathways to hypoxaemia, or other as yet unidentified processes.It is apparent that respiratory disease significantly changes drug disposition through a number of interacting mechanisms. These have not been adequately studied to provide a basis for clinical dosage adjustment, however, general principles are emerging: Drugs showing flow-dependent hepatic clearance (e.g. lignocaine/lidocaine, pethidine/meperidine, propoxyphene) and those drugs showing predominant renal clearance (aminoglycosides, digoxin) should be used with caution. Theophylline doses must be reduced on an empirical basis, as the mechanisms causing reduced clearance cannot be convincingly explained in terms of the pathophysiology of respiratory disease.The lungs must be added to the existing list of organs (liver, kidney, heart) whose dysfunction significantly affects drug disposition.

Displacement of lidocaine from serum α1-acid glycoprotein binding sites by basic drugs

SummarySince little is known of the number and types of binding sites on α1-acid glycoprotein (AAG) and because drug-drug protein binding interactions often fail to fit a simple model, a study of the effect of 9 known AAG binding drugs on lidocaine free fraction (LFF) was performed. Serum was obtained from 10 healthy males, pooled and various concentrations (from 0.15 to 1 000 µg/ml) of amitriptyline, bupivacaine, chlorpromazine, disopyramide, imipramine, meperidine, nortriptyline, propranolol and quinidine were added. LFF was determined by equilibrium dialysis at an initial lidocaine concentration of 2.0 µg/ml. LFF increased from 0.30±0.019 (mean ± SD) in the absence of displacing agents to maximum values ranging from 0.59 (nortriptyline) to 0.73 (bupivacaine). Plots of LFF vs. the logarithm of displacing drug concentration yielded simple sigmoidal curves in all cases. LFF was increased 50% by an initial bupivacaine concentration of 6.0 µg/ml with all other drugs requiring more than 10 µg/ml to increase LFF to that extent. Lidocaine binding in a 4.5 g/dl albumin solution was unaffected by concentrations of quinidine, meperidine, nortriptyline and bupivacaine up to 200 µg/ml. Addition of AAG to serum reduced LFF as expected. A plot of the reciprocal of bound drug concentration vs. the reciprocal of free drug concentration in the presence and absence of quinidine suggested a competitive binding interaction. These data indicate that the binding interactions between lidocaine and the various displacing compounds are not significantly complicated by cooperative effects and that, with the possible exception of bupivacaine, displacement of lidocaine by any of these drugs is unlikely to be of clinical significance.

Nonlinear pharmacokinetics of indocyanine green in the rabbit and rat

The pharmacokinetic behavior of indocyanine green (ICG) in the rabbit can be described by a two-compartment open model, allowing for saturable transport of drug to the peripheral compartment and for its first-order elimination from the peripheral compartment. Use of this model led to the prediction of the accumulation of ICG in the plasma of a rabbit following the administration of repeated i.v. injections. Furthermore, studies conducted in the rat were also consistent with this model. One characteristic of the model is that above certain dose levels, the accumulation of ICG in the liver (i.e., the peripheral compartment) should reach a maximum independent of dose during certain time periods. This prediction was confirmed in a series of studies in the rat. The findings presented in this report provide evidence that a single model may be capable of explaining the variety of pharmacokinetic characteristics which have been reported for ICG, at least in the dose range studied.

Mechanisms of nonlinear disposition kinetics of sulfamethazine

Five healthy male subjects received oral doses of 10 and 40 mg/kg of sulfamethazine (SMZ) approximately 14 days apart in a nonrandomized crossover study. Blood and urine samples were collected for at least 24 and 72 hr, respectively. All samples were assayed by the Bratton‐Marshall procedure for SMZ and apparent N‐acetylsulfamethazine (NSMZ). Recovery of total drug (SMZ + NSMZ) in urine was 88.9% following the low and 79.5% following the high dose. The low and high dose plasma concentration time curves were not readily superimposable (i.e., nonlinear kinetic behavior was observed). The data suggest that several mechanisms contribute to the nonlinearity. Specifically, a dose‐dependent decrease in absorption rate displaced the plasma concentration‐time curve to the right in some subjects, whereas apparent metabolic clearance (Clm) decreased with increasing dose (estimated assuming dose = amount of SMZ + NSMZ in urine to 72 hr) in all subjects (0.35 ml/min/kg for the low and 0.23 for the high dose). Still greater dose‐dependent effects were found when apparent Clm of unbound drug was determined, since free fraction rose from 0.11 to 0.30 over the observed plasma concentration range. Renal clearance (ClR) of SMZ appeared to be a complex function of time. In the low dose study it ranged from an average of 0.071 ml/min/kg at 2 hr to 0.146 mllminlkg at 6 hr after drug. After the high dose comparable values were 0.083 and 0.128. Interindividual variability and pronounced nonlinear kinetics of SMZ after 40 mg/kg suggest that this dose is probably a poor choice for the determination of acetylator phenotype.

Effect of carbohydrates on estimated hepatic blood flow

Recent experiments suggest that propranolol taken orally with a carbohydrate‐rich meal increases its apparent bioavailability by reducing first‐pass metabolism. It has been postulated that this increase in bioavailability may be secondary to a transient increase in hepatic blood flow (QH). To examine this hypothesis, we examined the effect of one of the carbohydrate meals (potato) tested in other propranolol studies on QH by measuring blood clearance (ClB) of indocyanine green (ICG). Ten minutes after eating 200 gm cooked potato, mean ICG blood clearance (ClB) in six subjects rose by 12% (range –13% to +41%). There also was a 10% mean increase (range –13% to +23%) in ICG ClB 60 min after the meal. It was then postulated that a larger carbohydrate meal might induce a more consistent and substantial increase in ICG ClB; therefore, five of the subjects were restudied after 400 gm potato. The increase in ICG ClB was of the order of that after 200 gm. Changes in QH of this magnitude would be expected to make a negligible contribution to the mean 50% increase in propranolol bioavailability reported by several investigators. It thus appears that factors other than change in QH play a dominant role in the reduced first‐pass metabolism of propranolol after a meal rich in carbohydrates.