Plasma protein binding increase

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]. 

Hypoalbuminemia and altered plasma protein binding increase free or unbound concentrations of drugs... 

Avoid aspirin, as it may increase free T4 and T3 levels by interfering with plasma-protein binding ° Fluid resuscitation... 

The drug is highly bound to albumin (approximately 90%) [91]. Protein binding is concentration dependent and decreases at high valproate concentration [91]. Free fraction plasma protein concentration increases from approximately 10% at 40 pg/mL to 18.5% at 130 pg/mL [91], Protein binding decreased markedly in elderly [92], in patients with renal failure [92], and in liver diseases [93]. 

Generally, plasma protein binding of acidic drugs (e.g., warfarin, pheny-toin) is decreased in CKD, whereas binding of basic drugs (e.g., quinidine, lidocaine) is usually normal or slightly decreased or increased. 

These refinements in our knowledge of brain penetration and CNS activity of drugs feature prominently in a major medicinal review of the blood-brain barrier [14]. In vivo perfusion studies on the rate of brain uptake of several non-steroidal anti-inflammatory drugs in rats with increasing concentration of albumin in the perfusate clearly demonstrate the effect of plasma protein binding on the rate (in addition to the extent at steady-state) of brain uptake [15]. 

However, the major contributing factor to the decreased renal clearance of total drug was increasing plasma protein binding with increasing lipophilicity. When the extent of plasma protein binding was taken into account, the imbound renal clear-... 

Phenylbutazone is metabolized by the liver at a rate of about 15-25% per day (B33), but plasma levels do not increase proportionately with increasing doses of the drug. The work of Burns et al. (B33) indicates that above a certain level plasma phenylbutazone concentrations plateau. The concentration at which this occurs varies among individuals and is probably a reflection of the level at which saturation of high-affinity plasma protein binding sites occurs. 

Absorption/Distribution - When acyclovir was administered to adults at 5 mg/kg by 1 hour infusions every 8 hours, mean steady-state peak and trough concentrations were 9.8 mcg/mL and 0.7 mcg/mL, respectively. When acyclovir was administered to adults at 10 mg/kg by 1 hour infusions every 8 hours, mean steady-state peak and trough concentrations were 22.9 mcg/mL and 1.9 mcg/mL, respectively. Absorption is unaffected by food. Bioavailability is between 10% and 20% and decreases with increasing doses. Concentrations achieved in CSF are approximately 50% of plasma values. Plasma protein binding is 9% to 33%. Acyclovir distributes widely in... 

The//(tissue) values are averaged for the species, this average is assumed to be the value for human, inserted back into the Oie-Tozer equation and combined with the measured value of /,(piasma) in human to obtain a predicted value for human VD. However, despite its increased complexity it does not offer additional accuracy over the above mentioned dog-human proportionality method and may only be most appropriate when plasma protein binding shows considerable inter-species variability. 

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