In plasma protein binding

Benet LZ, Hoener BA (2002) Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 71(3) 115—121... 

Finally, work that may facilitate understanding the role of oq-acid glycoprotein variants in inter-individual variations in plasma protein binding, pharmacokinetic behavior, and drug action has been described. A capillary zone electrophoresis method that allows for the determination of 11 intact forms (i.e., isoforms, glycoforms) of oq-acid glycoprotein has been described [84],... 

Some disease states (e.g., hyperalbuminemia, hy-poalbuminemia, uremia, hyperbilirubinemia) have been associated with changes in plasma protein binding of drugs. For example, in uremic patients the plasma protein binding of certain acidic drugs (e.g., penicillin, sulfonamides, salicylates, and barbiturates) is reduced. 

Mechanism of Action An adrenocorticosteroid that inhibits the release of inflammatory cells into nasal tissue, preventing early activation of the allergic reaction. Therapeutic Effect Decreases response to seasonal and perennial rhinitis. Pharmacokinetics Undetectable in plasma. Protein binding 98%-99%. The swallowed portion undergoes extensive metabolism. Excreted primarily through bile and, to a lesser extent, urine. Half-life 5.8 hr (nasal). 

J.J.H.M. Lohman, in Plasma Protein Binding of Drugs, Implications for Therapeutic Drug Monitoring, Thesis, Leiden, The Nerherlands (1986). 

It is important to note that the elimination half-life is a derived term, and any process that changes k will change the half-life of the drug. Factors that may affect pharmacokinetic parameters are discussed elsewhere, but in this example may include disease states, changes in urinary pH, changes in plasma protein binding, and coadministration of other drugs. 

Alterations in plasma vitamin concentrations have been observed in oral contraceptive users, and attributed to reduced absorption and changes in plasma protein-binding capacity (177). 

As bound concentration falls, the free concentration is more available for distribution and elimination, and as total concentrations are therefore lower, hypoalbuminaemia can lead to an increase in apparent volume of distribution. However, tissue distribution may also change in hepatic disease. This is illustrated by tolbutamide in viral hepatitis. No change was found in the volume of distribution of tolbutamide because changes in plasma protein binding were matched by changes in tissue binding [9]. 

Benet LZ, Hoener B. Changes in Plasma Protein Binding Have Little Clinical Relevance. J. Clin. Pharmacol. Ther. 2002 71 115-121. 

Although diastereoisomers, both quinine and quinidine, have similar physical properties (Fig. 18). In clinical studies, the renal clearance of quinidine was fourfold greater than that of quinine (57). No stereoselective differences in plasma protein binding were observed. The renal filtration and passive reabsorption of these two diastereoisomers should be similar since the compounds have similar octanol-water partition coefficients and pKa values (57). Therefore, stereoselective active renal secretion may be the mechanism responsible for the observed differences in the renal clearances of quinine and quinidine. 

The vast majority of studies on drug-protein binding have employed solutions of isolated plasma proteins or serum samples from healthy volunteers. Few data are currently available on the potential of enantio-selective disease-induced changes in plasma protein binding. This is the... 

S. Toon and W, F, Trager, "Pharmacokinetic implications of stereoselective changes in plasma-protein binding Warfarin-sulfinpyrazone," /. Pharm. ScL, 73 1671-1673 (1984). 

Age-related changes in drug distribution have been reported. The apparent volume of distribution is somewhat larger in newborns and infants than in adults. The estimated volume of distribution of sulfa-methoxypyridazine in newborns and infants is 0.47 and 0.36 L/kg, respectively, whereas the values are 0.20-0.26 L/kg in children, adults, and elderly subjects. The volume of distribution of chlordiazepoxide is substantially larger in the elderly (0.52 L/kg) than in the young (0.42 L/kg). The age-related difference in the volume of distribution may be due to a difference in plasma protein binding and/or in the relative size of body compartments. 

The extent of binding differences between isomers is most readily noted from ratios of fractions free in the plasma this ratio can be as high as three (Table 2). Recognizing that plasma protein binding impacts on drug distribution and elimination, differences in plasma protein binding between stereoisomers may lead to misinterpretation of pharmacokinetic comparisons between isomers, unless protein binding of the isomers is considered. 

Alfentanil is 90% protein bound, and variabUity in protein binding can affect its actions. In 10 patients who received standardized anesthesia and alfentanil to a target concentration of 150 ng/ml for postoperative analgesia interindividual variation in plasma protein binding explained at least 39% of the interindividual variability in alfentanil requirements (13). There was a high incidence of adverse effects seven patients had emesis and five had urinary retention. 

Routledge PA, Stargel NW, Kitchell BB, Barchowski A, Shand DG. 1981. Sex-related differences in plasma protein binding of lignocaine and diazepam. Br. J. Clin. Pharmacol. 11 245-250. 

However, other examples showed less success (51-53). The reason is that the method cannot be used when there are interspecies differences in drug sensitivity, in metabolism, and in plasma protein binding. An improvement in the use of the preclinical data allowed bypassing some of these limitations, as reported by several authors (54-57). 

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