Blood plasma proteins, drug binding

Cisplatin shows biphasic plasma decay with a distribution phase half-life of 25 to 49 minutes and an elimination half-life of 2 to 4 days. More than 90% of the drug is bound to plasma proteins, and binding may approach 100% during prolonged infusion. Cisplatin does not cross the blood-brain barrier. Excretion is predominantly renal and is incomplete. 

Pharmacokinetic and pharmacodynamic differences between drug isomers present another important issue relating to drug metabolism. Individual enantiomers of drugs administered as racemates show different pharmacokinetic profiles due to differences in metabolic clearance rates and binding affinities to blood plasma proteins [34]. 

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]. 

Some AEDs, especially phenytoin and valproate, are highly bound to plasma proteins. When interpreting a reported concentration for these drugs, it is important to remember that the value represents the total (i.e., bound and unbound) concentration in the blood. Because of differences in the metabolism of these drugs, the clinical effects of altered protein binding are different for different drugs. 

Normally, 88% to 92% of phenytoin is bound to plasma protein, leaving 8% to 12% unbound. The unbound component is able to leave the blood to produce the clinical effect in the CNS, produce dose-related side effects in the CNS and at other sites, distribute to other peripheral sites, and be metabolized. Certain patient groups are known to have decreased protein binding, resulting in an increased percentage of drug that is unbound. These patient groups include ... 

The original proposal of the approach, supported by a Monte Carlo simulation study [36], has been further validated with both pre-clinical [38, 39] and clinical studies [40]. It has been shown to be robust and accurate, and is not highly dependent on the models used to fit the data. The method can give poor estimates of absorption or bioavailability in two sets of circumstances (i) when the compound shows nonlinear pharmacokinetics, which may happen when the plasma protein binding is nonlinear, or when the compound has cardiovascular activity that changes blood flow in a concentration-dependent manner or (ii) when the rate of absorption is slow, and hence flip-flop kinetics are observed, i.e., when the apparent terminal half-life is governed by the rate of drug input. 

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]. 

Binding of the drug to protein molecules in blood plasma... 

The most frequent protein in the plasma, at around 45 g is albumin. Due to its high concentration, it plays a crucial role in maintaining the blood s colloid osmotic pressure and represents an important amino acid reserve for the body. Albumin has binding sites for apolar substances and therefore functions as a transport protein for long-chain fatty acids, bilirubin, drugs, and some steroid hormones and vitamins. In addition, serum albumin binds Ca "" and Mg "" ions. It is the only important plasma protein that is not glycosylated. 

Sulfalene is also a very long-lasting bacteriostatic sulfanilamide with a broad spectrum of antimicrobial activity. It is used for the same indications as sulfadoxine. Its half-life is about 150-200 h. This drug binds to proteins in the plasma to a lesser degree than other sulfanilamides, which ensures its high concentration in the blood in a free form. Therefore, only one dose of sulfalene needs to be taken one time per week. Synonyms of this drug are celfizin, sulfamethopyrazine, sulfamethoxypyrazine, and others. 

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