Changes In Plasma Protein Binding Research Articles

The effect on the rat isolated atria of amiodarone in the presence of either ouabain or verapamil.

Amiodarone causes a decrease in the rate of contraction of the rat isolated atria and has a negative inotropic action in the paced preparation. Interactions occur between amiodarone and ouabain and amiodarone and verapamil. It is possible that the clinically reported drug interaction with amiodarone may have a component of direct interactions on the myocardium rather than solely changes in plasma protein binding.

Changes in Plasma Protein Binding of Drugs after Blood Collection from Pregnant Women

Changes in Plasma Protein Binding of Drugs after Blood Collection from Pregnant Women

Changes in Plasma Protein Binding of Drugs after Blood Collection from Pregnant Rats

Changes in Plasma Protein Binding of Drugs after Blood Collection from Pregnant Rats

Evidence for a factor in the sera of patients with nonthyroidal disease which inhibits iodothyronine binding by solid matrices, serum proteins, and rat hepatocytes.

We have measured the plasma protein binding of [125I]T4 and [125I]T3 in several groups of patients using assays of equilibrium dialysis and binding by dextran-coated charcoal carriedout under conditions of physiological pH. Subjects included 45 patients with nonthyroidalillnesses (NTI), 5 patients with hyperthyroidism, 5 with hypothyroidism, 1 with familial low T4-binding globulin (TBG), and 11 healthy controls. Both test results wereexpressed as the ratio of nonprotein-bound to protein-bound hormone, which was normalizedto the average ratio obtained for the control group [normalized dialysis ratio (NDR); normalized charcoal binding ratio (NBR)]. Our data suggest that for subjects with thyroid disease or alterations in TBG, both tests reflect similar changes in plasma protein binding and did not differ significantly from each other [low TBG; T4 NDR, 2.39; T4 NBR, 2.37; hyperthyroid: T4 NDR, 1.70 ± 0.29; T4 NBR, 1.53 ± 0.26; hypothyroid: T4 NDR, 1.10 ± 0.09; T4 NBR, 0.94 ± 0.11 (mean ± SD)]. Among NTI subj...

Pharmacokinetic Factors Influencing Variability in Human Drug Response

It is well recognised that the clinical response to drug administration varies widely between individuals and that most of this variability is pharmacokinetic in origin. In general, variability arises because of inter-individual differences in rates of drug absorption, drug distribution and elimination, either by metabolism or excretion. Variability of drug response is also a consequence of a variety of drug interactions which may influence pharmacokinetic parameters. Among the many factors which are responsible for the variation in human drug response, age is relatively important. As a consequence of impaired metabolism and excretion the inter-individual variation in the kinetic of many drugs is much greater in the elderly. Also the degree of plasma-protein binding, in turn, influences the distribution, action, metabolism and renal excretion of drugs. Thus changes in plasma protein binding of drugs, e.g. in diseased states, may give rise to altered pharmacokinetic and possibly altered drug response. The above factors influencing variability in drug response are discussed with particular reference to examples of non-steroidal antiinflammatory drugs used in the treatment of rheumatic diseases.

Effect of changes in plasma protein binding on half-life of drugs

Effect of changes in plasma protein binding on half-life of drugs

Effect of plasma protein and tissue binding on the biologic half-life of drugs.

It is now generally appreciated that there can be pronounced interindividual differences in plasma protein binding of many drugs because of genetic,13 environmental (drug interaction),11 and pathologic7 factors and aging.1 Pharmacokinetic theory has been developed to relate quantitatively the effect of changes in plasma protein binding to changes in the elimination kinetics of drugs.8,14 In the case of drugs that are eliminated almost entirely by hepatic biotransformation with linear (apparently nonsaturable) kinetics not limited by organ perfusion rate, it has been shown that the total clearance (Cl) is directly proportional to the free fraction of drug in plasma (fp), i.e.,

The effects of urine pH and plasma protein binding on the renal clearance of disopyramide.

To ascertain whether the renal clearance of disopyramide (pKa = 8.36) is affected by urine pH, the disposition kinetics of disopyramide were compared during excretion of acidic and alkaline urine following both single dose intravenous (2mg/kg) and oral (5 mg/kg) administration to 4 healthy male volunteers. No significant difference was observed in the plasma concentration-time curve of disopyramide. The mean 72 hour recovery of disopyramide and its N-deisopropyl metabolite (MND) in urine was 55.1 and 20.3% of the dose respectively, with no apparent difference between the two routes of administration or pH of urine. Renal clearance of disopyramide was found to vary with time, which is partly the result of a concentration dependent change in plasma protein binding. The unbound fraction of drug in plasma varied from 0.32 to 0.72 between 0.4 to 4microgram/ml concentration. However, time-dependent change in renal clearance of disopyramide persists even after correction for plasma protein binding.

Plasma protein binding of diazepam and tolbutamide in chronic alcoholics.

The increased incidence of drowsiness in hypoalbuminemic patients administered diazepam and more rapid clearance of tolbutamide in cirrhotics may be due to changes in plasma protein binding. The binding of diazepam and tolbutamide was studied by equilibrium dialysis at 37degreesC over a total drug concentration range of 1 to 10 mug/ml and 50 to 300 mug/ml, respectively, in plasma from 21 normal and 14 alcoholic subjects. At 1 mug/ml, diazepam plasma protein binding (+/- S.D.) was 98.5+/-0.4 per cent in normals and 97.8+/-1.2 per cent in alcoholics; at 100 mug/ml, tolbutamide binding was 97.8+/-0.3 per cent in normals and 95.1+/-4.2 per cent in alcoholics. For both agents at all concentrations, the binding to plasma from alcoholics was significantly decreased (P less than 0.01-less than 0.02). The extent of binding of both drugs was dependent on the albumin concentration. These findings suggest that important changes in pharmacologic effect, distribution, and clearance of diazepam and tolbutamide can be anticipated in alcoholics with hypoalbuminemia.

Pharmacokinetics in the elderly.

The elderly are generally considered to be different from young people in terms of drug response and this applies particularly to quantitative differences. While altered drug handling is a major potential source of difference in responsiveness to drugs, the relative contribution of pharmacokinetics and pharmacodynamics to this difference is not clear. In the present review we have examined the available data on pharmacokinetics in the elderly. In the past, data pertaining to animal models have been extrapolated to man and in the absence of human experimentation these assumptions have tended to hold sway. This is best exemplified by studies on drug absorption. The absorption of actively transported substance may in fact be diminished in the elderly. However, most drugs are absorbed by passive diffusion and the recently available evidence in man indicates that there is no age-dependent change. While definitive data on the effect of old age on drug metabolising ability in animals is available, no direct assessments have been made in man. Many of the studies carried out using drug plasma half-life and clearance assessments are complicated by changes in distribution. This is best illustrated by a definitive study with diazepam, in which marked prolongation of plasma half-life was accompained by an increase in apparent volume of distribution in the elderly. This latter change influences plasma drug clearance and, possibly, drug concentration at its site of action. Thus, the implications for drug effect of such changes in volume of distribution remain to be clarified. In theory, the rate of elimination of antipyrine should provide a good index of drug metabolising ability. Both plasma half-life and clearance values suggest a decreased in metabolism in the elderly. No other drug has been studied as intensively and the evidence for a diminished metabolism of other drug in the elderly is less definite. Thus, while it is likely that the metabolism of some drugs is imparied in old age, it is not possible at this time to generalise with regard to the effect of age on drug metabolising ability in man. It is also difficult to generalise about age-related changes in plasma protein binding of drugs. With some drugs, binding to plasma protein does not appear to be altered and for two drugs-warfarin and phenytoin, the findings of different investigators conflict. Diminution of glomerular filtration rate, renal plasma flow and associated tubular function with age have been well documented. Drug clearance comparisons between old and young have been carried out for only three renally excreted drugs-digoxin, propicillin and sulphamethizole. With digoxine and sulphamethizole, the evidence is that renal excretion is diminished in the elderly. With propicillin, changes in volume of distribution predominate, resulting in higher plasma levels in the elderly but similar percent recovery in urine...