Influence of Binding on Drug Metabolism and Distribution*

Abstract

Plasma as a streaming albumin depot or a transport organ?. , . the great bulk of drug may enter into 'silent' combinations. . . . The difficulties inherent in studying interactions with the proteins of fixed tissues present a sharp contrast to the readiness with which those of the plasma lend themselves to investigation A. Goldstein ' * Our purpose is to discuss the significance of binding of drugs to proteins from the parochial view of a clinical pharmacologist. In particular, we intend to evaluate how binding to plasma proteins influences the fate of drugs in man.t Our theme is that protein binding is only one of a family of physicochemical properties that are needed to predict or interpret in vivo or in vitro observations with drugs. These properties include pK,, (in aqueous medium and not in some exotic solvent), partition coefficients, stability, and so on. Many of the points we raise here have been discussed in other When faced with a new drug we usually proceed as follows: 1. A method of analysis (if possible, including radioactive tracer) is developed. 2. Experiments are performed in animals (we prefer dogs because of ease of sequential sampling and other factors). Measurement of concentrations of drug and metabolites in plasma, blood, urine, and so on are made after a reasonable intravenous dose chosen on the basis of methodology and pharmacology. Parameters such as half-life in plasma, urinary excretion, volume of distribution, tissue distribution, and so on are derived. 3. We also determine physicochemical properties, including binding to dog plasma, human plasma, and albumin, pK,, ~tability,!'~ solubility, partition coefficient, and others. At this point and at subsequent stages we review the strategy of the methods of analysis in terms of specificity, sensitivity, choice of isotope, position of label in the molecule, ease, cost, and so on. 4. Oral administration and different dosages are evaluated in animals.From the above information and the structural features of the drug (functional groups, size of rings, molecular weight) we can now make certain predictions about the fate in man. H. Bennhold 43. O9Plasma Half-Life. This is likely to be longer in man than in the dog. Renal Clearance. From binding data at various plasma levels, processes such as glomerular filtration are calculable. If we exclude secretion and if the * Partly supported by United States Public Health Service Grant GM 14270.i ' We restrict ourselves to molecules smaller than molecular weight 1000 and exclude endogenous substances, such as L-dopa, hormones, and so on. * Reference 62.t pK.s were determined in aqueous solution. t K,=partition coefficients for the system-peanut oil and Sorenson buffer (pH § F. and P. for human serum albumin were given as 1.0 and 0.4 and 2.28 and for phenylbutazone and oxyphenbutazone, respectively." A single K, 7.4). x M-'was also reported'' for phenylbutazone (1.17 X 1od M-').

Age and the pharmacokinetics of angiotensin converting enzyme inhibitors enalapril and enalaprilat.

“…Drug distribution is a physicochemical interaction between drugs and tissues. It is affected by plasma protein binding (Dayton et al, 1973) which may fall in the elderly (Greenblatt et al, 1982), by aqueous and lipid solubility, by body weight and surface area, and by the lean/fat body mass ratio (Klotz, 1976). Enalaprilat is not extensively protein bound (< 80%) (Gomez et al, 1983).…”

Thiopentone‐induced changes in the contraction pattern of vascular smooth muscle: the influence of albumin

“…1). Whether the free fraction of thiopentone is determined by equilibrium dialysis (Dayton et al, 1973;Christensen et al, 1980Christensen et al, , 1983 or by ultrafiltration (Andreasen, 1973;Christensen et al, 1980) the fraction is remarkably constant over a wide concentration range. The values of thiopentone binding obtained here are in good agreement with the values which could be anticipated from these previous studies.…”

CSF Concentrations and Serum Protein Binding of Carbamazepine and Carbamazepine‐10, 11‐epoxide in Epileptic Patients

“…Protein binding may for several reasons be an important determinant of drug therapeutic and toxic effects (Curry, 1970: Gillette, 1973Dayton, Israili & Perel, 1973;Wardell, 1974). Modification of plasma protein binding due to diseases or displacing effects of other drugs has been shown to alter dramatically the toxic effects of several compounds (Reidenberg & Affrine, 1973;Anton, 1973).…”