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Pharmacokinetics of sulfaethidole in the rat: Nonlinear multicompartment solution

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Abstract

Sulfaethidole distribution and elimination in the rat was studied over a 90-fold dose range. This experimental design produced marked nonlinearity in the binding of Sulfaethidole to proteins in both interstitial fluid and plasma. Using a multicompartmental model consisting of binding of Sulfaethidole to plasma and interstitial fluid proteins, Sulfaethidole distribution in the body could be simulated. Urinary and biliary elimination of Sulfaethidole depended on the unbound drug mass in the plasma and urine flow. The results confirm the central role of the unbound species in the distribution and elimination of drugs with marked binding to plasma proteins.

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Abbreviations

A 1 :

amount of drug in plasma (mg)

A 2 :

amount of drug in interstitial fluid (mg)

A 3 :

amount of drug in poorly perfused tissues (mg)

A 4 :

amount of drug in highly perfused tissues (mg)

fu 1 :

fraction of total drug in plasma unbound (dimensionless)

fu 2 :

fraction of total drug in interstitial fluid unbound (dimensionless)

fb 11 :

fraction of drug bound to first binding site on plasma protein (dimensionless)

fb 12 :

fraction of drug bound to second binding site on plasma protein (dimensionless)

fb 21 :

fraction of drug bound to first binding site on interstitial fluid protein (dimensionless)

fb 22 :

fraction of drug bound to second binding site on interstitial fluid protein (dimensionless)

K d,1 :

apparent dissociation constant of first binding site on protein (dimensionless)

K d,2 :

apparent dissociation constant of second binding site on protein (dimensionless)

B −1max,11 :

inverse of maximal binding capacity of first binding site on plasma protein (ml/mg)

B 12−1max :

inverse of maximal binding capacity of second binding site on plasma protein (ml/mg)

B −1max,21 :

inverse of maximal binding capacity of first binding site on interstitial fluid protein (ml/mg)

B −1max,22 :

inverse of maximal binding capacity of second binding site on interstitial fluid protein (ml/mg)

k 12 :

fractional transport rate of unbound drug from plasma to interstitial fluid (h−1)

k 21 :

fractional transport rate of unbound drug from interstitial fluid to plasma (h−1)

k 23 :

fractional transport rate of unbound drug from interstitial fluid to poorly perfused tissues (h−1)

k 32 :

fractional transport rate of unbound drug from poorly perfused tissues to interstitial fluid (h−1)

k 10 :

fractional rate of elimination of unbound drug from plasma (h−1)

k 010 :

value during the first 210 min

k 110 :

value after 270 min, linearly increased between 210 and 270 min (Eq. 5)

fup t :

fraction of instantaneous binding of drug between plasma unbound drug and highly perfused tissue (dimensionless)

V p :

plasma volume (ml)

V is :

interstitial fluid volume (ml)

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Authors and Affiliations

  1. Second Department of Medicine, Helsinki University Central Hospital, 00290, Helsinki 29, Finland

    Matti Kekki & Risto J. K. Julkunen

  2. Department of Pharmacology, University of Helsinki, 00170, Helsinki 17, Finland

    Risto J. K. Julkunen

  3. Electrical Engineering Laboratory, Technical Research Centre of Finland, 02150, Espoo 15, Finland

    Hannu Pohjanpalo

Authors
  1. Matti Kekki
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  2. Risto J. K. Julkunen
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  3. Hannu Pohjanpalo
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Kekki, M., Julkunen, R.J.K. & Pohjanpalo, H. Pharmacokinetics of sulfaethidole in the rat: Nonlinear multicompartment solution. Journal of Pharmacokinetics and Biopharmaceutics 10, 27–51 (1982). https://doi.org/10.1007/BF01059182

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