Total Plasma Drug Concentrations Research Articles

A comparative study of intravenous and rectal administration of propofol in piglets

To compare the effectiveness of propofol given intravenously and rectally, ten piglets received propofol intravenously. On the next day, the same piglets and five other piglets were given suppositories containing propofol. Serial blood samples were collected for the analysis of propofol plasma concentration. The time course of the total plasma drug concentration was fitted into a bi-exponential function using a least square fitting regression computer programme. The volume of distribution was 2.5-2.8 l.kg-1, mean elimination half-life, 23.9 min and mean clearance 0.08 l.kg-1.min-1. The mean bioavailability by the rectal route was low. In contrast to the intravenously administered propofol, none of the piglets slept when given propofol rectally, reflecting the extremely low plasma propofol concentration. In veterinary medicine, propofol would seem to be clinically valuable for inducing intravenous anaesthesia, but would be ineffective when given rectally. The findings indicate that with the dosage forms used here, propofol would be clinically ineffective if given rectally to human infants and children.

Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease.

1. Ten patients with bilateral knee joint effusions were treated topically with a gel containing 1 g diclofenac/100 g (80 mg three times daily). They were randomized to receive diclofenac gel to one knee and a placebo gel preparation to the other knee. 2. Diclofenac was assayed in synovial fluid and blood plasma by GC/ECD as the pentafluorobenzyl-ester derivative. 3. Total concentrations of diclofenac in synovial fluid (day 4) were significantly higher in the diclofenac gel treated knee than in the contralateral placebo treated knee (25.5 +/- 3.6 ng ml-1 vs 21.6 +/- 2 ng ml-1; P less than 0.05). These concentrations were lower than total plasma drug concentrations (40.6 +/- 4.7 ng ml-1, n = 10, P less than 0.01). Unbound concentrations of diclofenac in synovial fluid from either the diclofenac gel treated or the placebo treated knee were not significantly different from each other or from plasma free concentrations (115 +/- 16 and 99 +/- 12 vs 108 +/- 19 pg ml-1). 4. Clinical parameters showed improvement of joint mobility and a small reduction of swelling (circumference) in both knees with time. However, the differences between knees were not significant. 5. We conclude that direct transport of diclofenac from the skin into the ipsilateral knee joint after cutaneous application is minimal. Distribution seems to be predominantly via the blood. Whether the observed improvements of clinical parameters were due to drug effects or to the spontaneous course of the underlying disease cannot be distinguished.

Effect of non‐linear plasma protein binding on unbound and total plasma phenylbutazone concentrations in cows

The influence of plasma protein binding on unbound and total phenylbutazone concentrations in cows was examined employing data from the literature. Protein binding parameters (number of binding sites and affinity constants) were generated by computer analysis to characterize the concentration-dependent plasma protein binding of phenylbutazone. Unbound plasma phenylbutazone concentrations were calculated from total plasma drug concentrations observed after administration of a single dose of phenylbutazone to cows. Pharmacokinetic parameters for unbound phenylbutazone were obtained. Parameters characterizing the plasma protein binding and pharmacokinetics of unbound phenylbutazone derived from single-dose administration were then used to predict unbound and total drug concentrations after multiple-dose administration of phenylbutazone. Total plasma phenylbutazone concentrations predicted from single-dose pharmacokinetic parameters agreed well with observed values following multiple-dose administration of the drug. Thus, the results of this analysis demonstrate that the non-linear pharmacokinetics of phenylbutazone in the cow can be attributed to the concentration-dependent plasma protein binding of the drug.

Plasma Protein Binding of Drugs in Pregnancy and in Neonates

Plasma protein binding of drugs has important implications for drug disposition and action since it is the first, and controlling, step in drug distribution. Physiological changes in pregnancy include significant changes in plasma composition which affect drug binding and subsequent drug response; the extent of these changes depends on the stage of gestation. Both albumin and alpha 1-acid glycoprotein fractions are reduced, and consequently the binding of both acidic and basic drugs may be affected. This may lead to difficulties in maintaining adequate plasma concentrations of highly protein-bound drugs, since the measurement of total drug concentration in plasma may no longer be a valid indicator for dose adjustment. The newborn infant displays a continually changing plasma profile. The presence of fetal proteins and endogenous substrates known to interfere with drug binding can lead to unexpected complications due to a higher than expected 'free' drug fraction. Furthermore, a decrease in the affinity of albumin for bilirubin during this period may lead to bilirubin displacement by drugs such as diazepam, sulphonamides and salicylate, resulting in clinical jaundice which would not occur beyond the neonatal period. Plasma composition and its effect on drug binding should be taken into account when prescribing highly protein bound drugs with narrow therapeutic: toxic ratios.

Perioperative variability of binding of lidocaine, quinidine, and propranolol after cardiac operations

This study examined the effect of changes in plasma concentrations of total protein, albumin, alpha 1-acid glycoprotein, and free fatty acids occurring after heart operations on the protein binding of chemically basic drugs. Plasma protein and free fatty acid concentrations were measured simultaneously with in vitro determinations of the protein binding of lidocaine, quinidine, and propranolol: immediately before operation, immediately on weaning from cardiopulmonary bypass, on arrival in the recovery room, and 12, 24, 72, and 120 hours postoperatively. Initial decreases in the concentrations of all proteins were followed by a rise in alpha 1-acid glycoprotein to 254% of baseline at 72 to 120 hours. The free fractions of drug were initially increased to 168% of baseline for lidocaine, 206% for quinidine, and 200% for propranolol and fell progressively with time, reaching sustained troughs of 65% for lidocaine, 50% for quinidine, and 57% for propranolol at 72 to 120 hours. Regression analysis indicated a major influence of changing alpha 1-acid glycoprotein concentrations on free fractions of all three drugs, with a smaller effect of albumin that reached statistical significance only for lidocaine. There were no significant perioperative changes in plasma concentrations of free fatty acids when the in vitro effects of heparin were controlled. In conclusion, sequential changes in plasma protein concentrations after cardiac operations predictably alter the protein binding of lidocaine, quinidine, and propranolol and should be considered when interpreting total plasma drug concentrations.

Saliva concentrations of disopyramide cannot substitute the drug's plasma concentrations.

For many drugs the salivary concentration corresponds to the free plasma drug concentration, which may be more closely related to drug activity or toxicity than the total plasma drug concentration. In this study a preliminary investigation was undertaken to determine the feasibility of monitoring saliva levels of disopyramide, an antiarrhythmic drug, for clinical and toxicological purposes. Single oral doses of this compound were administered to healthy volunteers. Stimulated mixed saliva and plasma levels were measured by the EMIT technique. The concentrations of disopyramide in the stimulated mixed saliva tended to be lower than those found in the corresponding plasma sample (fp 0.3-0.5), and the saliva-to-plasma concentration ratio increased with a decreasing salivary pH (pH 6.89, S/P = 0.25; pH 8.15, S/P = 0.08). The correlation between the saliva and the total plasma concentrations was significant but relatively poor, however. Consequently, mixed salivary disopyramide concentrations are a poor indicator of plasma concentrations, even if correction is made for pH change.

Relationship between saliva and free and total plasma theophylline concentrations in patients with chronic airflow obstruction.

Total plasma and mixed stimulated saliva theophylline concentrations (by high performance liquid chromatography) and free plasma theophylline concentrations (by equilibrium dialysis) were measured in simultaneously collected samples from 32 outpatients receiving chronic oral theophylline treatment, who had received the drug at least two hours before sampling. There was a close relationship between saliva and total plasma theophylline concentration and between total saliva and free plasma concentration. The mean saliva to total plasma drug concentration ratio was 0.69 (SE 0.09) and the mean difference between paired saliva and free plasma concentration was 0.65 (0.17) microgram/ml. It is concluded that stimulated mixed saliva provides a simple, non-invasive method of assessing total (and free) plasma theophylline concentrations during chronic oral treatment. The therapeutic range for saliva, corresponding to the generally accepted total plasma concentration range (10-20 micrograms/ml), is approximately 7-14 micrograms/ml.

Uptake and/or binding of tricyclic antidepressants in human red cells

The factors affecting the red blood cells (RBC) uptake and/ or binding of tricyclic antidepressants imipramine (IMI) and desmethylimipramine (DMI) were investigated under in vitro conditions. The time course of drug distribution indicated that equilibrium between RBC and medium is reached rapidly. The uptake and/or binding of IMI and DMI to RBC was not saturable and RBC/medium ratio was unaffected by pH, nature of monovalent cations or by the presence of therapeutic concentrations(5–50 ng/ ml) of antipsychotic drugs. In the protein-free medium, RBC/ medium ratio of DMI was X ± SE = 2.58 ± 0.08 ( n=5) and that of IMI was 7.38 ± 0.12 (n=6). However, RBC/plasma ratio of DMI was 0.78 ± 0.04 (n=7) and IMI ratio was 0.64 ± 0.03 (n=9). The RBC/ medium ratio was linearly related to free fraction of IMI in a buffer containing 60 mg/ml of human serum albumin with various concentrations of alpha 1-acid glycoprotein (r=0.971, n=7). These results suggest that in the absence of proteins the lipid solubility of antidepressants is the main determinant factor in RBC uptake and/or binding, whereas, in the presence of proteins, free fraction of the drug plays the major role. Hence, the RBC/plasma ratio of antidepressants may correlate with treatment outcome in clinical studies better than total drug concentration in plasma.

Binding of diazepam and desmethyldiazepam to plasma protein: concentration-dependence and interactions.

The binding of diazepam (DZ) and its major metabolite desmethyldiazepam (DMDZ) to plasma protein was evaluated in a series of controlled in vitro studies using equilibrium dialysis. Free fraction (FF) of both drugs alone changed significantly with total plasma drug concentration, but the increased FF (reduction in binding) did not occur until concentrations considerably exceeded those encountered during typical therapeutic use. Increasing concentrations of one drug at a time tended to increase FF for the other, although the effects were, at most, of borderline significance. Simultaneously increasing concentrations of both drugs led to significantly increased FF for both. Thus, DZ and DMDZ appear to bind to the same site or sites on plasma albumin. Binding is concentration-independent within and considerably above the usual therapeutic range.

Effect of plasma protein and tissue binding on the time course of drug concentration in plasma

We have studied by digital computer simulation the effect of concentration-dependent plasma protein and tissue binding on the time course of drug concentrations (both unbound and total) in plasma following rapid injection of a drug whose elimination rate is proportional to either free or total drug concentration in plasma, assuming instantaneous equilibration of the drug between vascular and nonvascular spaces. The following observations were made when elimination rate was assumed to be a function of free drug concentration: (a) when plasma protein binding is nonlinear and there is either no tissue binding or linear tissue binding, log concentration-time plots of free drug are always concave whereas such plots for total (sum of free and bound) drug can be convex, almost linear, or concave (apparently biexponential) depending on the plasma protein binding parameters relative to the initial concentration; (b) linear tissue binding in association with nonlinear plasma protein binding can reduce the concavity or enhance the convexity of log total concentration-time plots. When drug elimination rate was assumed to be a function of total concentration in plasma, nonlinear plasma protein binding in association with linear or no tissue binding yielded convex log total concentration-time plots which could sometimes be described by Michaelis-Menten kinetics. In general, drug concentration-dependent changes in the apparent volume of distribution resulting from nonlinear plasma protein and (where applicable) tissue binding have a pronounced effect on the slope of log total plasma concentration-time plots. It appears that under clinically realistic conditions an otherwise marked curvature of such plots, due to nonlinear plasma protein binding, may in fact be dampened or overcome by linear tissue binding.

Influence of acute viral hepatitis on disposition and plasma binding of tolbutamide.

To study the influence of acute hepatic disease on the disposition of tolbutamide, we measured tolbutamide plasma protein binding and pharmacokinetic parameters after intravenous administration of the drug to 5 subjects during and after apparent recovery from acute viral hepatitis. Although during the acute phase of illness protein binding of the drug decreased in all, volume of distribution of tolbutamide (0.15 +/- 0.03 L/kg) did not change. Clearance based on total concentration of tolbutamide in plasma increased in all subjects during the acute phase of study (26 +/- 5.4 ml/hr/kg) in comparison to the recovery phase (18 +/- 2.8 ml/hr/kg, p less than 0.02). Protein binding decreased after unconjugated bilirubin was added to plasma from the recovery phase, but not to the extent observed during the acute phase of illness at comparable levels of bilirubin. Clearance based on unbound drug concentration, calculated by dividing the observed plasma clearance by the fraction of unbound drug in plasma, did not differ significantly between the 2 study phases (300 +/- 47 and 260 +/- 39 ml/hr/kg). These observations suggest that the increase in clearance based on total drug concentration in plasma during hepatitis can be attributed solely to decreased plasma binding. This decrease in binding may be attributed in part, but not entirely, to increased combination of bilirubin during illness. The concentration of unbound drug in plasma at steady-state is determined by the rate of drug administration and the clearance based on unbound drug. If this clearance does not change during hepatic disease, no dosage alterations for tolbutamide and other comparable drugs are necessary to maintain a constant concentration of unbound drug.