Unbound plasma fraction

In obese women, the AAG concentrations are doubled, and the unbound plasma fraction of propranolol is 30 /o lower than that in women with normal body weight.f In the obese, the albumin concentrations, and phenytoin binding are normal, whereas diazepam binding is slightly reduced. In undernourished or hospitalized patients, the AAG concentrations are 30 0% higher than those in unhospitalized patients, and the propranolol free fraction is reduced by approximately, 30%. A marked decrease in albumin concentration has been reported in malnutrition, and it seems associated with a reduction in protein synthesis. ... 

AAG is a protein known as an acute phase reactant. As a result of inflammation, injury during physiological trauma, and stress,an increase in the binding capacity of AAG is commonly observed in patients. For a drug that is highly bound, an increase in AAG plasma levels will result in a significant decrease in unbound plasma fraction. Examples include propranolol, lidocaine, and disopyra-mide after myocardial infarction and propranolol and chlorpromazine in Crohn s disease. 

An increase in AAG concentrations after an acute myocardial infarction causes a decrease in the unbound plasma fraction of propranolol and lidocaine (non-restrictively cleared drugs). With intravenous or oral... 

A decrease in concentration of proteins and an increase in concentration of free fatty acids in plasma are observed in hyperthyroidism. For propranolol and warfarin, an increase of up to 20-30 % in the unbound plasma fractions has been reported. ... 

Note that the maximal free ETPC (not published in the Omata et al. study) was estimated based on a 4 pg/mL plasma concentration and a 39 % unbound plasma fraction (see Collinsworth et al. 1974 Routledge et al. 1980)... 

A similar strategy was employed to identify a DPP-IV inhibitor (6) with good in vivo potency in a mouse model of diabetes [44], Plasma protein binding, as assessed by shift assay (50% serum), was presented for all final compounds. The compound selected as having the best overall profile was active in vivo at 0.1 mg/kg. The activity at 1 h post-dose was consistent with the free drug principle - total plasma concentration 269 nM murine-free fraction 4% unbound plasma concentration 11 nM in vitro potency versus murine DPP-IV 6nM. 

The pharmacological effect is exerted by unbound drug molecules. Thus, if only total drug concentrations (e.g. in plasma) are analysed, one should consider whether these measurements are reflective of the concentrations at the site of action. If the unbound drug fraction is more relevant than the total concentration, e.g. because of saturable protein binding, it should be used as the independent variable in the PK-PD model. Figure 5 shows the consistency of the PK-PD relationship between total, as well as unbound quinine concentration and hearing impairment in man. 

Usually the ratio of unbound plasma concentration (Cu) of the toxicant to total toxicant concentration in plasma (C) is the fraction of drug unbound, f , that is,... 

Only the unbound fraction in plasma is filtered in the kidney. Therefore, the rate of filtration is the product of glomerular filtration rate (GFR) and unbound plasma concentration. For a drug which is only filtered and all filtered drug is excreted into the urine, the renal clearance (CLr) is the rate of filtration product ... 

In characterising the protein binding several parameters of a drug can be experimentally determined - the unbound plasma concentration (Cu), the bound plasma concentration (cb), the fraction bound (fb), and the fraction unbound (fu). The determination can be performed at one defined concentration (e.g. 10 iM) or within a range including the pharmacological and toxicological relevant concentrations. 

The distribution of drugs is affected by the circulating plasma that transports them to sites of action, metabolism, and excretion. After absorption, most drugs are partially or almost totally bound to plasma and tissue proteins. The portion that is protein bound is pharmacologically inactive. It serves as a reservoir from which the usually much smaller unbound active fraction can be replenished as the free drug is metabolized and excreted (51). 

Renal disease (uraemia) may increase the volume of distribution of acidic drugs that extensively bind to plasma albumin (e.g., phenytoin, valproic acid, naproxen, phenylbutazone, furosemide). As decreased protein binding would increase the unbound (free) fraction in the plasma, the therapeutic concentration range (based on total drug concentration) would be lower than the usual... 

Siro distributes primarily mto blood cells (95%), with only 3% and 1% distributing into plasma, lymphocytes, and granulocytes, respectively, The extensive and avid binding of Siro to the ubiquitously distributed intracellular FK-binding proteins accounts for the high blood to plasma Siro concentration ratio. Approximately 2.5% of the Siro within the plasma fraction is unbound. ... 

There s also a pharmacokinetic way to analyze the likely outcome of binding displacement interactions on pharmacodynamic outcomes. Steady-state unbound plasma concentrations can be defined in terms of a drug s clearance (CL), the fraction of drug absorbed (F), the dose (D), and the dosing interval, t. 

Significant differences also are present between the Vdss of bupivacaine enantiomers (R S = 1.56), but not between prilocaine enantiomers. The difference in unbound fraction in plasma between prilocaine enantiomers was statistically significant but negligible (S R=1.04) (Table 3) [207], which explains the lack of difference in Vd of the enantiomers. On the other hand, the unbound fractions of bupivacaine enantiomers differed significantly both statistically and numerically (R S ratio of 1.5). When the unbound CL of bupivacaine enantiomers was determined, the value for the R enantiomer was actually less than that of antipode, indicating the influence of plasma protein binding in determining total (bound + unbound) plasma concentrations of the enantiomers [208]. 

Vss, apparent volume of distribution at steady state f p, fraction drug unbound in plasma (C ) , average free (unbound) plasma drug concentration at steady state (Cp) , average total (bound plus free) plasma drug concentration at steady state. ... 

The Poulin and Theil (homogeneous and extracellular), Berezhkovskly and Rodgers, Leahy, and Rowland methods for calculating partition coefficients are among those available in the program. The Poulin and Theil and Berezhkovskly models take into consideration the volume fractions of water, phospholipids, neutral hpids, and unbound protein fractions in tissues and plasma (fut and fup). The Poulin and Theil models do not take into consideration unbound proteins. 

Cmin,ss Minimum plasma concentration at steady state fu Fraction unbound in plasma... 

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