Rapid equilibration of warfarin between rat tissue and plasma

Benya, Theodore J.; Wagner, John G.

doi:10.1007/bf01066920

Cited by 13 publications

(5 citation statements)

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“…These types of plots are n o t recommended. Since the binding of drugs to plasma proteins is extremely rapid (Keen, 1971) and the binding of some drugs to tissues is also extremely rapid (see Wagner, 1973 for d i p h e n h y d r a m i n e in the rat; and Benya and Wagner, 1975 for w a r f a r i n in the rat), one might expect the model to hold f o r l o w d o s e s in some cases. It should be noted that if one derives equations for a similar model, but with several different types of tissues, the same general form for equation 17 is obtained, except that there are additional terms in the d e n o m i n a t o r for each type of tissue (see Wagner, 1971).…”

Section: E S T I M a T I O Nmentioning

confidence: 99%

“…There has been much discussion in the literature on the effects of plasma protein binding on the distribution, elimination, and activity of drugs (Anton and Solomon, 1973;Benya and Wagner, 1975;Coffey, 1972;Garrett, 1972;Keen, 1972;KrHger-Thiemer, 1966 and1968;Levy and Yacobi, 1974;Martin, 1965;Wagner, 1971 and1975) and these citations are not intended to be complete. The review of Keen (1971) not only discussed the mPartly supported by Public Health Service Grant 5-P-II-GM 1559 and partly by Grant IROIAAOO683-possible effects of plasma protein binding, but also discussed the possible effects of tissue binding.…”

mentioning

confidence: 99%

“…He cited data showing that cardiac glycosides which are highly bound to plasma proteins are also highly bound to tissues. A similar situation has been reported for diphenhydramine (Wagner, 1973 andAlbert et el., 1975) and for warfarin in the rat (Benya and Wagner, 1975;Yacobi and Levy, 1975). Several authors (Coffey, 1972;Garrett, 1972;Keen, 1971;Kr~ger-Thiemer, 1966 and1968;Levy and Yacobi, 1974;Martin, 1965;Yacobi and Levy, 1975) have developed mathematical and p h a r m a c o k i n e t i c models and equations which incorporate plasma protein binding.…”

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Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution, apparent elimination rate constants and clearances

Wagner

1976

Eur J Clin Pharmacol

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A simple pharmacokinetic model, incorporating linear plasma protein binding, linear tissue binding, and first order elimination of free (unbound) drug, was studied. If Clp is the plasma clearance, Vf is the "true" volume of distribution of free drug, beta is the apparent elimination rate constant, sigma is the fraction of the drug which is free in plasma, f is the fraction of the drug which is free in the entire body, kf is the intrinsic elimination rate constant for free drug, and AoTB is the initial amount of drug which is bound to tissues, then the model indicates that the following relationships hold: (1) Clp = Vfsigma kf; (2) beta = f kf; and Vdext = (sigma/f) Vf. Only sigma, and not f, can be measured experimentally. Dividing Clp by sigma provides an estimate of the intrinsic clearance of free drug, Vfkf. A plot of Vdext versus sigma has an intercept equal to Vf, and the ratio of the slope/intercept is an estimate of AoTB/Aof, where Aof is the initial amount of free drug (equal to Vf times initial concentration of free drug in plasma). Thus, an estimate of AoTB may be obtained. Dividing the intrinsic clearance by Vf provides an estimate of kf. Thus, theoretically, estimates of Vf, kf, AoTB and f may be obtained. The variables are not separated when beta is plotted versus sigma, and curvature of such plots is expected; no useful information is obtained from such plots.

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Section: E S T I M a T I O Nmentioning

confidence: 99%

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Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution, apparent elimination rate constants and clearances

Wagner

1976

Eur J Clin Pharmacol

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“…Nor is drug distribution necessarily limited by extensive plasma binding. For example, the rate of warfarin tissue distribution in rats was very rapid; within I minute after intravenous injection most of the dose was bound to tissues, even though warfarin was computed to be 99.0 to 99.1 % bound in plasma (Benya and Wagner, 1975). Consequences of altered drug plasma protein binding on hepatic drug clearance depend upon whether albumin serves as a transport protein or as a storage depot for the drug (Gillette, 1973).…”

Section: Restrictive Eliminationmentioning

confidence: 98%

Protein Binding of Coumarin Anticoagulants in Disease States

Bachmann

Shapiro

1977

Clinical Pharmacokinetics

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Excessive hypoprothrombinaemia accompanying the use of coumarin oral anticoagulants may be associated with changes in coumarin disposition which, in turn, can arise from changes in coumarin plasma protein binding. Coumarins bind extensively to human serum albumin with primary binding affinity constants of approximately 10 5 LI mole. The nature of coumarinalbumin binding is chiefly hydrophobic although hydrogen bonding and electrostatic interactions are also involved. Differences in analytical techniques and conditions have given rise to varied values for numbers of binding sites, binding affinity constants, and extent of albumin, serum, or plasma binding. However, the extent of coumarin binding appears 10 hold relatively constant over expected therapeutic concentration ranges. The plasma binding of warfarin is ~.~ ~ J:.hflJac/e,.is~4 _by_m(J/'k(!d interindividual differences.App~--"e-"t ~oiumeso/di;lri;;uiiOnorCouma,.iils-approxTmaie -t-'ie~ Size oTilie albu;mn~sjiai:i/ and are apparently dose independent with the exception perhaps of dicoumarol (bishydroxycoumarin) which has been reported 10 exhibit a decreasing apparent volume of distribution with increasing dose. Volumes of distribution increase as the free coumarin fraction increases. Plasma albumin serves as a storage depot for coumarins, and their hepatic elimination is restrictive; that is, limited /0 the free fraction perfusing the liver. Increases in the free fraction of coumarins· will be accompanied by increased clearance rates, and changes in hepatic blood flow rates will have negligible effects on coumarin half lives.Conditions which may be associated with diminished coumarin binding to albumin and enhanced elimination include: thyrotoxicosis, hyperbilirubinaemia, fasting, stress, diabetes mellitus, acute myocardial infarction, cirrhosis, hepatic tumours, and renal dysfunction. However, the only pathological condition in man which is clearly accompanied by decreases in coumarin plasma binding, is renal dysfunction. The cause of diminished warfarin binding in patients with renal dysfunction has not been elucidated, although the presence of an endogenous warfarin-binding inhibitor seems likely.It is not clear whether conditions leading to increases in coumarinfreefractions require adjustments in coumarin dosage schedules. Theoretical considerations suggest that neither increased disbribution volumes nor clearance rates associated with increasing the free coumarin fraction will lead to changes in the average steady state plasma levels of free drug. A preliminary study in patients with renal dysfunction suggests that warfarin dosage regimens do not require adjustment in such patients. However, increases in the coumarin free fraction, apparent volume of distribution, and clearance rate may be aI/ended by increases in peak unbound coumarin levels and decreased trough levels of unbound coumarin thereby 'making anticoagulant control more difficult. Ultimately, these possibilities must be confirmed or rejected on the basis of additional clinical investigations.

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“…Figure 2 shows some nonclassical linear pharmacokinetic models in which there are reversible transfers between the terminal input compartment and one of the disposition compartments; the models shown also have reversible transfers between all input compartments, but these are not essential to produce the effects to be described. In models I-A and II-A, compartment 1 represents small intestinal contents as the absorption site; compartment 2 represents not only plasma but also tissues which bind the drug, such that the drug in tissue is in equilibrium with free drug in plasma water and there is a constant tissue concentration/free drug concentration in plasma water ratio (3); compartment 3 of model II-A represents tissues and/or other fluids of distribution and is analogous to the usual second compartment of the classical "two-compartment open model." In models I-B, I-C, II-B, and II-C, compartment 1 represents the stomach contents, and compartment 2 represents the small intestinal contents; compartment 3 in these models is analogous to compartment 2 in models I-A and II-A, and compartment 4 in these models is analogous to compartment 3 in model II-A.…”

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Linear pharmacokinetic models and vanishing exponential terms: Implications in pharmacokinetics

Wagner

1976

Journal of Pharmacokinetics and Biopharmaceutics

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A series of models more closely related than classical models to known facts aboutdrug absorption and disposition are presented. It is shown that mathematically such models require the same number of exponential terms in the equation describing the plasma concentration following intravenous administration as in that describing the plasma concentration following oral administration. However, it is also shown that one or two of the exponential terms of the intravenous, and sometimes the oral, equation often are relatively unimportant and appear to vanish on stripping or fitting of data. This phenomenon leads to ambiguity concerning which model to assign to one or more sets of data. The number of potential models in a given situation has now been greatly increased. It is also shown that if data obey these models then neither the Wagner-Nelson nor the Loo-Riegelman method provides estimates of absorption rate constants when the At/Vp, t data are analyzed by conventional methods. KEY WORDS: inseparable input and disposition portions of models; vanishing exponential terms; drug absorption and disposition models; absorption rate constants; model-independent pharmacokinetics; potyexponential computer fitting. INTRODUC~ON One method of classifying linear pharmacokinetic models is shown in Figs. 1 and 2. Figure 1 shows some classical linear pharmacokinetic models in which transfer from input to disposition compartments occurs in only one direction. This leads to a separation of input and disposition functions, and the Laplace transform methods of Benet (1) and Vaughan and Trainor (2)

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Rapid equilibration of warfarin between rat tissue and plasma

Cited by 13 publications

References 6 publications

Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution, apparent elimination rate constants and clearances

Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution, apparent elimination rate constants and clearances

Protein Binding of Coumarin Anticoagulants in Disease States

Linear pharmacokinetic models and vanishing exponential terms: Implications in pharmacokinetics

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