For about half a century, the binding of drugs to plasma albumin, the "silent receptor," has been recognized as one of the major determinants of drug action, distribution, and disposition. In the last decade, the binding of drugs, especially but not exclusively basic entities, to another plasma protein, alpha 1-acid glycoprotein (AAG), has increasingly become important in this regard. The present review points out that hundreds of drugs with diverse structures bind to this glycoprotein. Although plasma concentration of AAG is much lower than that of albumin, AAG can become the major drug binding macromolecule in plasma with significant clinical implications. Also, briefly reviewed are the physiological, pathological, and genetic factors that influence binding, the role of AAG in drug-drug interactions, especially the displacement of drugs and endogenous substances from AAG binding sites, and pharmacokinetic and clinical consequences of such interactions. It can be predicted that in the future, rapid automatic methods to measure binding to albumin and/or AAG will routinely be used in drug development and in clinical practice to predict and/or guide therapy.

A review of the clinical applications and of the disposition of probenecid in man, including drug interactions, is presented. Probenecid is the classical competitive inhibitor of organic acid transport in the kidney and other organs. There are 2 primary clinical uses for probenecid: as a uricosuric agent in the treatment of chronic gout and as an adjunct to enhance blood levels of antibiotics (such as penicillins and cephalosporins). Adsorption of probenecid is essentially complete following oral administration. The drug is extensively metabolised by glucuronide conjugation and by oxidation of the alkyl side chains; oxidation of the aromatic ring does not occur. The half-life of probenecid in plasma (4 to 12 hours) is dose-dependent. Renal excretion is the major route of elimination of the metabolites; excretion of the parent drug is minimal and is dependent on urinary pH. Probenecid and its oxidised metabolites are extensively bound to plasma proteins, mainly to albumin. Tissue concentrations (based on animal studies) are generally lower than plasma concentrations. Most of the drug-drug interactions involving probenecid are due to an effect on the kidney-block of transport of acidic drugs. Similarly probenecid affects the tubular secretion of a number of acidic endogenous substances by the kidney. Probenecid is also involved in the block of transport of acidic metabolites of catecholamines, for example homovanillic and hydroxyindoleacetic acids, in the brain. There are a number of analytical procedures for the assay of probenecid. These are based on spectrophotometry, spectrofluorometry, gas and liquid chromatography and radioimmunoassay.

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-').

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Pharmacokinetic studies in 4 children with hypo glycemia who required diazoxide therapy revealed a half‐life of the drug in blood of 9.5 to 24 hmlrs. The blood level of diazoxide in these children while receiving maintenance therapy was 15 to 50 p.g per milliliter. Hyperglycemia and acidosis developed in one of these patients in the presence of a persistent blood level above 100 ug per milliliter. Twenty‐four hour urinary excretion of unchanged drug in 2 patients was 20 and 33 per cent of the initial dose, and 80 per cent in one patient on maintenance. In order to investigate the fate of the drug better, 3H‐diazoxide was purified for use in adult volunteers and animals. The half‐life of the drug in plasma of 2 adults was 24 and 36 hours. In these subiects as much as 94 per cent of the radioactive dose was recovered in the urine. About half the radioactivity in urine was present as unchanged drug. The plasma half‐life of 3H‐diazoxide in rats and dogs was much shorter than in man.

The effect on blood pressure of giving hydralazine orally, 300 mg per day divided into 2, 3, and 4 doses, was studied in 4 hypertensive patients. In the treatment of chronic hypertension, hydralazine is conventionally given in 4 divided doses per day, and this schedule of prescribing

Triamterene is a pteridine used therapeutically as a diuretic. In order to better understand variations in effect and toxicity of triamterence in individuals, the fate of the drug in man was investigated. Both nonradioactive and 14C-labeled forms of the drug were administered, and specific methods of analysis were used to separate the parent compound from its metabolite. Individual variation in absorption, binding, and elimination was noted. The drug was excreted in bile as well as urine. Rapid and extensive metabolism of the agent occurred after oral and intravenous doses in healthy adult men. The peak plasma levels of the drug after an oral dose (200 mg) were under 0.3 microng/ml, but the concentration of the primary metabolite. (2,4,7-triamino-6-p-hydroxyphenylpteridine) was higher. The urinary excretion of the metabolite was at least three times that of the parent drug.