Effect of Binding to Plasma Proteins on the Distribution, Activity and Elimination of Drugs

Keen, P.

doi:10.1007/978-3-642-65052-9_10

Cited by 46 publications

(32 citation statements)

References 46 publications

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“…The transport of antibiotics from serum into interstitial fluid and tissues is influenced by a number of factors, including serum protein binding and lipid solubility of the compound (16,18). The capillary bed of most tissues contains small fenestrations that permit ready passage of substances of molecular weight up to about 1,000.…”

Section: Discussionmentioning

confidence: 99%

Relation Between Lipophilicity and Pharmacological Behavior of Minocycline, Doxycycline, Tetracycline, and Oxytetracycline in Dogs

Barza

Brown

Shanks

et al. 1975

Antimicrob Agents Chemother

196

120

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Four tetracyclines were studied in dogs to determine the relation between their lipophilicity and various other pharmacological characteristics. Lipid solubility correlated inversely with the mean concentration of drug in arterial plasma and renal uptake and excretion, and directly with the biliary concentration gradient (level in bile/level of free drug in serum). Only the more lipophilic congeners minocycline and doxycycline passed the blood-brain and blood-ocular barriers in detectable concentrations. Mean levels of minocycline in the brain exceeded those of doxycycline by almost threefold; the difference was of borderline statistical significance (P = 0.05 to 0.1). Lipophilicity correlated inversely with the concentration of antibiotic in renal medulla but not in renal cortex or in the liver. When intestinal loops containing saline, milk, or 10% Gelusil were studied, the only combination exhibiting striking intraluminal accumulation was doxycycline in milk. These results indicate that lipophilicity correlates with many, but not all, of the transport characteristics of tetracycline antibiotics.Since the discovery of the tetracycline antibiotics over 25 years ago, a number of molecular modifications have been made with a view to improving tissue distribution, prolonging their half-life, augmenting intestinal absorption, and enhancing their antibacterial activity. Many of these objectives have been met in minocycline and doxycycline (6,9,10,25,26,34,41). Of additional interest is the fact that neither of these tetracyclines appears to require a major adjustment in dose in the presence of renal failure (6, 41), suggesting that they are extensively eliminated by nonrenal routes. Doxycycline has been demonstrated to be excreted extensively via the intestine (41). The data relative to minocycline, however, are inconclusive, and biliary excretion (29), intestinal excretion (6), and metabolic degradation (25) The purpose of the present investigation was to compare minocycline, doxycycline, tetracycline, and oxytetracycline with regard to their uptake and excretion by the liver and kidney, and their penetration into ileal contents, brain, cerebrospinal, and ocular fluids. The studies were carried out in a canine model that has been employed in previous investigations in our laboratory (5).MATERIALS AND METHODS Surgical preparation. The surgical preparation procedure has been described previously (5). Healthy mongrel dogs weighing 20 to 29 kg were anesthetized. Intravascular cannulas were placed in the femoral artery and vein and left renal, portal, and hepatic veins for aspiration of blood. Clotting was prevented by flushing the cannulas with heparin. Flow probes (Statham Co., Los Angeles, Calif.) were applied to the left renal and portal veins. Mean arterial pressure was recorded with a pressure transducer. Both ureters and the common bile duct were catheterized, and the cystic duct was ligated.Several additional procedures not performed in previous studies of this model were carried out. The terminal ileum was mobi...

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Section: Discussionmentioning

confidence: 99%

Relation Between Lipophilicity and Pharmacological Behavior of Minocycline, Doxycycline, Tetracycline, and Oxytetracycline in Dogs

Barza

Brown

Shanks

et al. 1975

Antimicrob Agents Chemother

196

120

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“…The extent of protein binding of a sub stance depends on its physicochemical properties, on the concentration and type of binding protein, and on the presence of endogenous or exogenous inhibitors [5,9]. The binding may change rapidly in the same individual.…”

Section: Discussionmentioning

confidence: 99%

Drug Binding to Plasma Proteins During Human Pregnancy and in the Perinatal Period

Herngren¹,

Ehrnebo²,

Boréus³

1983

Dev Pharmacol Ther

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Plasma protein binding of one acidic drug, cloxacillin, and one basic drug, alprenolol, was determined by equilibrium dialysis at + 37 °C during pregnancy and the 1st postnatal week in 12 women and their newborn infants and in 7 nonpregnant women (controls). A significant increase in fraction free cloxacillin in maternal plasma occurred during pregnancy already from the 2nd trimester compared to the controls (p <0.01) and was most pronounced at delivery (median values 0.126 and 0.069, respectively). A similarly increased fraction free cloxacillin was found in cord blood (median value 0.108) which further increased during the 1 st postnatal week (range 0.112-0.164). In maternal plasma the binding capacity returned to the values of the controls during the same time period. The binding of cloxacillin was significantly correlated with the concentration of albumin (p < 0.01). High correlation was also found between binding of the basic drug alprenolol and concentration of orosomucoid (p < 0.005). This was most obvious in the newborn infants with low concentrations (range 0.1-0.3 g/1) and in the mothers during the puerperium with high concentrations of orosomucoid (range 0.7-2.5 g/1). On the basis of plasma protein binding data in the mother and her child, a maternal to fetal plasma concentration ratio was calculated. For cloxacillin this ratio was close to unity (1.03), while it was significantly above unity for alprenolol (1.72). At equilibrium, therefore, the total plasma concentration of alprenolol in the mother can be expected to exceed the concentration in her infant.

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“…It is commonly assumed that only drugs present in free form (not bound to plasma), can be cleared by the liver; this type of elimination is called restrictive (19,20,21) and holds true if E ,::;; free fraction. If E > free fraction, non-restrictive elimination occurs, and more than the free fraction of the drug can be functionally extracted by the liver (19,20,21).…”

Section: Selection Of Controlsmentioning

confidence: 99%

“…If E > free fraction, non-restrictive elimination occurs, and more than the free fraction of the drug can be functionally extracted by the liver (19,20,21). Any liver disease accompanied by associated reduction of plasma binding (see table I) will lead to an increased efficiency of the hepatic extraction.…”

Section: Selection Of Controlsmentioning

confidence: 99%

Influence of liver disease on the elimination of drugs

Klotz

1976

European Journal of Drug Metabolism and Pharmacokinetics

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Av.ail~bl~literature contains some contradictory clinical evidence about the effect of liver disease on the metabolism a.nd elImmatIo~of~rugs. !n the ma!~rity of the cases, drugs are more slowly eliminated in patients with hepatic dysfunction, such as cirrhosis or viral hepatitis. However, there is no single biochemical liver test for the proper characterization of the functional s.tatus of the. liver. Since all drugs behave differently pharmacokinetically, no predictions can be made fr?~th~results with one particular drug for other drugs--each drug has to be investigated separately. Due to the slower elimination of. drugs observed in pa~ients with liver disease, caution should be applied in prescribing drugs with more ?ron?unced biological effects, especially those with a small therapeutic index. When calculating maintenance doses or infusion rates for a longer treatment, dosage reduction and a close drug monitoring seem to be advisable.

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Effect of Binding to Plasma Proteins on the Distribution, Activity and Elimination of Drugs

Cited by 46 publications

References 46 publications

Relation Between Lipophilicity and Pharmacological Behavior of Minocycline, Doxycycline, Tetracycline, and Oxytetracycline in Dogs

Relation Between Lipophilicity and Pharmacological Behavior of Minocycline, Doxycycline, Tetracycline, and Oxytetracycline in Dogs

Drug Binding to Plasma Proteins During Human Pregnancy and in the Perinatal Period

Influence of liver disease on the elimination of drugs

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