Drug distribution plasma protein binding

Drug Interactions During Distribution Displacement from Plasma Protein Binding Sites... 

Lombardo F, Obach RS, Shalaeva MY and Gao F. Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data. J Med Chem 2002 45 2867-76. 

The distribution of a drug in the body is largely driven by its physicochemical properties and in part for some compounds by the contribution of transporter proteins [17]. By using the Oie-Tozer equation and estimates for ionization (pfCj). plasma protein binding (PPB) and lipophilicity (log quite robust predictions for the volume of distribution at steady state (Vdss), often within 2-fold of the observed value, can be made [18]. 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

In cases where plasma protein binding varies across the species, allometric scaling should be based upon the volume of distribution of unbound drug. The considerably... 

A combination of various properties of antipyrine gives it an advantage over other microsomal enzyme metabolizing drugs. These include high oral availability useful for non-invasive oral administration, lack of plasma protein binding which prevents environmental clearance variability, and fast distribution... 

Absorption/Distribution - Oral absorption is nearly complete. Peak plasma levels are attained at approximately 3 hours. The plasma half-life ranges from 12 to 27 hours after multiple oral doses. Steady-state levels are approached in 3 to 5 days once at steady-state, no accumulation occurs during chronic therapy. Plasma levels are approximately proportional to dose. In patients with congestive heart failure (CHF NYHA class III), the rate of flecainide elimination from plasma is moderately slower than for healthy subjects. Plasma protein binding is about 40% and is independent of plasma drug level over the range of 0.015 to about 3.4 mcg/mL. 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

Plasma Protein Binding and Volume of Distribution Determination, Prediction and Use in Early Drug Discovery... 

Table 2. Plasma protein binding and drug distribution ...

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