The free drug hypothesis, which states that only the unbound moiety of drug in blood is available for tissue diffusion, is discussed according to recent investigations. In some experimental conditions, it must be assumed that part of the protein-bound drug in plasma is extracted during a single passage through the organ studied. The mechanisms underlying these observations are not unequivocal and remain hypothetical. In the liver, high-affinity binding sites for serum albumin have been demonstrated, and they would explain the high extraction by liver of endogenous and exogenous compounds. However, these experiments measure the unidirectional transfer of a drug from the vascular to the extravascular space in non-steady-state conditions. Hence, in steady-state conditions, the free drug hypothesis cannot be ruled out because it is supported by numerous pharmacokinetic studies.
Prostaglandin (PG) E2 and F2 alpha synthesis by isolated glomeruli and papillary homogenates prepared from control, salt-loaded, and salt-depleted rats was measured in vitro with and without added arachidonic acid using specific radioimmunoassays. Glomeruli from salt-depleted rats synthesized less PGE2 and more PGF2 alpha than glomeruli from control rats under both conditions. The effect of sodium restriction could be attributed to stimulation of glomerular 9-keto-PGE2 reductase activity unrelated to a change in the concentration of this enzyme. High salt diet had no effect on PG synthesis by glomeruli. Papillary homogenates prepared from salt-loaded rats synthesized more PGE2 than those from control rats both with and without added arachidonic acid. This finding suggests an effect of high salt diet at a stage further than phospholipid deacylation. Low salt diet had no effect on PG synthesis by papillary homogenates. The physiological control of PG synthesis in response to changes in the NaCl content of the diet is, therefore, different for the glomeruli and the papilla.
The binding of the two drugs isradipine and darodipine, chemically related to dihydropyridines and potent calcium channel blockers, was studied in vitro to isolated plasma proteins, erythrocytes and human serum. The two drugs were strongly bound to serum proteins (up to 97%), mainly to human serum albumin (HSA), α1-glycoprotein (AAG) and lipoproteins (VLDL, LDL and HDL). Their bindings to AAG were saturable with high affinity constants (isradipine 498,000 M–1, darodipine = 155,000 M–1; n = 1). The binding of these drugs to HSA, VLDL and HDL was unsaturable, but it was saturable on LDL. In blood the drugs partitioned in erythrocytes, 16% for isradipine and 14.8% for darodipine.
The myocardial accumulation and elimination pharmacokinetics of PN 200-110 (PN) were investigated in the single pass isolated perfused rat heart by two methods. A direct method, radioactivity measurement in myocardial tissue after various perfusion times, and an indirect method, concentration determination in coronary effluent, by fractionary collection of samples, during infusion and elimination periods. Both methods showed that the myocardium could be considered as a one-compartment model with regard to PN pharmacokinetics. The perfusion with a modified Krebs-Ringer (MKR) solution containing 1 nM of (+/-)PN 200-110 and [3H]-(+)PN 200-110 as radioactive tracer, led to an accumulation of about 61.4 fmol.mg-1 myocardial tissue at steady-state. The effect of protein binding on the uptake and pharmacokinetic parameters of PN has been investigated in this isolated perfused heart (IPH) model. binding of PN decreased as a function of increasing bovine serum albumin (BSA) levels in the perfusion solution. As a matter of fact, the mean steady state myocardial concentration of PN was decreased by 42.9, 56.2, 76.5, 83.9 and 95.5% for respectively, 1, 2.5, 6, 10 and 40 g.l-1 of BSA. In the same way, the free fraction, the apparent volume of distribution (Vd) and the distribution and elimination half-lives were decreased. On the contrary, the elimination rate constant was increased.
Summary— The free drug hypothesis, which states that only the unbound moiety of drug in blood is available for tissue diffusion, is discussed according to recent investigations. In some experimental conditions, it must be assumed that part of the protein‐bound drug in plasma is extracted during a single passage through the organ studied. The mechanisms underlying these observations are not unequivocal and remain hypothetical. In the liver, high‐affinity binding sites for serum albumin have been demonstrated, and they would explain the high extraction by liver of endogenous and exogenous compounds. However, these experiments measure the unidirectional transfer of a drug from the vascular to the extravascular space in non‐steady‐state conditions. Hence, in steady‐state conditions, the free drug hypothesis cannot be ruled out because it is supported by numerous pharmacokinetic studies.
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