Distribution studies plasma protein binding

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]. 

There have been several reports where plasma protein binding data was used in the prediction of in vivo properties of compounds. Two papers noted that the ability to predict in vivo clearance from in vitro microsome data was greatly improved when a plasma protein binding term was included [64,65]. In another study, binding to phospholipids and human serum albumin was assessed by HPLC retention times (on IAM and HAS columns, respectively) and used to predict volume of distribution [66]. 

Pharmacokinetics The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies. The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues. 

Distribution addresses the transfer of the drug compound from the site of administration to the systemic circulation and then to bodily tissues. Both in vitro and in vivo studies are informative here. In vitro studies, for example, examine plasma protein binding. In vivo studies use whole body autoradiography that can display visually how much drug has reached different parts of the body. Transfer of the drug compound in milk to an infant and across the placenta is also studied. 

Davis et al. (2000) discuss the problem of correcting certain pharmacokinetic values for the fraction unbound in plasma, advising caution in the approach as it may lead to spurious correlations. Values for clearance or volume of distribution of compounds have been reported in previous studies to correlate with log K. In some of these studies the correlations use values for clearance or volume of distribution that have been corrected for the fraction unbound in plasma. However, the fraction unbound in plasma is itself dependent on log K. Therefore, it is important to check that these reported correlations are genuine and not merely a reflection of the relationship between plasma protein binding and log K. ... 

Vinnikova [22, 23] described the spectrophotometric determination of mefenamic acid at 490 nm after conversion to its colored complex with Fast Red B salt at pH 6.60 (phosphate buffer). The method was applied for the determination of free and bound mefenamic acid, and found to be useful for studying the blood plasma protein binding, absorption, distribution, metabolism, and excretion of mefenamic acid. 

Many of the drug monographs contain a new section entitled Disposition in the Body. This section details die absorption, distribution, and excretion of the drug, notes the major metabolites and therapeutic and toxic plasma concentrations, and gives values for pharmacokinetic parameters such as half-life, volume of distribution, clearance, and protein binding. In addition, abstracts from published clinical studies and case histories are included. 

Studies of the distribution of [3H]ginsenoside Rgl following intravenous injection have been performed in mice (80). Tissue radioactivity was greatest in the kidney, followed by the adrenal gland, liver, lungs, spleen, pancreas, heart, testes, and brain. Plasma protein binding was 24%, and tissue protein binding was 48% in the liver, 22% in testes, and 8% in the brain. 

Valproic acid is rapidly distributed and the plasma protein binding is concentration dependent (18). As previously noted, valproic acid is extensively metabolized, primarily in the liver, with about 30-50% of the drug excreted as the glucuronide (phase II metabolism) in the urine, about 30-40%by the phase I mitochondrial j3-oxidation pathway, and about 10-20% by microsomal cytochrome P450-mediated hy droxylation/dehydrogena-tion of the side chain that provides the major phase I metabolites (36). The metabolites of valproic acid have been thought to be the cause of a rare, but fatal hepatotoxicity (35). The synthetic ( )-2,4-diene VPA has been shown to induce the same hepatic microve-sicular steatosis seen in patients, in chronic administration studies in rats (36). The ultimate causative factor (s) of hepatoxicity of valproic acid currently remain undefined (28,29). 

The relationship between chemical structure, lipophilicity, and its disposition in vivo has been extensively studied. These include solubility, absorption potential, membrane permeability, plasma protein binding, volume of distribution, and renal and hepatic clearance. Activities used in quantitative structure-activity relationships (QSAR) include chemical measurements and biological assays. QSAR currently are applied in many disciplines, with many pertaining to drug design and environmental risk assessment. 

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