Blood-brain barrier plasma protein binding

Zidovudine was the first drug of the class. It is a dideoxythymidine analog. It has to be phos-phorylated to the active triphosphate. This triphosphate is a competitive inhibitor of HIV reverse transcriptase. By incorporation into viral DNA it also acts as a chain-terminator of DNA synthesis. Mutations in viral reverse transcriptase are responsible for rapidly occurring resistance. Zidovudine slows disease progression and the occurrence of complications in AIDS patients. It is readily absorbed. However, first pass metabolism reduces its oral bioavailability with some 40%. It readily crosses the blood-brain barrier. Plasma protein binding is about 30%. Zidovudine is glucuronidated in the liver to an inactive metabolite. Its elimination half-life is 1 hour. 

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]. 

Levodopa, a dopamine precursor, is the most effective agent for PD. Patients experience a 40% to 50% improvement in motor function. It is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa requires active transport by a large, neutral amino acid transporter protein from the small intestine into the plasma and from the plasma across the blood-brain barrier into the brain (Fig. 29-2). Levodopa competes with other amino acids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements and administration of these should be spaced by at least 2 hours from the levodopa dose.1,8,16,25... 

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]. 

Data on distribution give an indication of whether a particular tissue may be exposed to the substance or not. The extent of chemical distribution into tissues depends on the extent of plasma protein and tissue binding and this may vary among species. This is also the case for passage of chemicals into the brain, which is protected by the blood-brain barrier. 

Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter, which is responsible for the transport of large amino acids across the blood-brain barrier. 

Distribution - Tinidazole is distributed into virtually all tissues and body fluids and crosses the blood-brain barrier. The apparent volume of distribution is approximately 50 L. Plasma protein binding of tinidazole is 12%. Tinidazole crosses the placental barrier and is secreted in breast milk. 

Keywords ADME-Tox solubility Caco-2 absorption blood-brain barrier human intestinal absorption oral bioavailability plasma protein binding QSAR... 

Lithium is readily absorbed from the gastrointestinal tract, reaching a peak plasma level in 2 to 4 hours. Distribution occurs throughout the extracellular fluid with no evidence of protein binding. Passage through the blood-brain barrier is limited, so that cerebrospinal fluid levels are 50% of plasma levels at steady state. 

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. 

When a drug reaches the circulation, it quickly distributes outside the capillary beds into well-perfused tissues but may distribute slowly or not at all to less-accessible tissues protected by barriers, such as the brain. The volume of distribution is the ratio of the amount of drug in the body divided by the drug concentration in plasma once a pseudo-equilibrium is estabhshed between blood and tissues. For small molecules, a low volume of distribution generally signifies extensive plasma protein binding that restricts distribution outside the capillary bed, while a large volume of distribu-... 

Once absorbed, foreign compounds may react with plasma proteins and distribute into various body compartments. In both neonates and elderly human subjects, both total plasma-protein and plasma-albumin levels are decreased. In the neonate, the plasma proteins may also show certain differences, which decrease the binding of foreign compounds, as will the reduced level of protein. For example, the drug lidocaine is only 20% bound to plasma proteins in the newborn compared with 70% in adult humans. The reduced plasma pH seen in neonates will also affect protein binding of some compounds as well as the distribution and excretion. Distribution of compounds into particular compartments may vary with age, resulting in differences in toxicity. For example, morphine is between 3 and 10 times more toxic to newborn rats than adults because of increased permeability of the brain in the newborn. Similarly, this difference in the blood-brain barrier underlies the increased neurotoxicity of lead in newborn rats. 

Fate of fatty acids The free (unesterified) fatty acids move through the cell membrane of the adipocyte, and immediately bind to albumin in the plasma. They are transported to the tis sues, where the fatty acids enter cells, get activated to their CtA derivatives, and are oxidized for energy. [Note Active transport of fatty acids across membranes is mediated by a membrane fatty acid binding protein.] Regardless of their blood levels, plasma free fatty acids cannot be used for fuel by erythrocytes, which have no mitochondria, or by the brain because of the imperme able blood-brain barrier. rr f-... 

Liu X, Smith BJ, Chen C, et al. Use of a physiologically based pharmacokinetic model to study the time to reach brain equilibrium an experimental analysis of the role of blood-brain barrier permeability, plasma protein binding, and brain tissue binding. J Pharmacol Exp Ther 2005 313(3) 1254—1262. 

Nonallergic hyperreactivity corresponds to the traditional notion of food intolerance. It is a syndrome in which dysfunctions are similar to those observed in the course of allergic diseases, induced by various mechanisms, excluding immunology-related factors. Nonallergic hyperreactivity occurs more frequently than allergy. Morbidity rate in children is approximately 20%-50%, while in adults it is estimated to be approximately 20%. Attention is drawn to the fact that the enzymatic system in children is less mature, so the capacity to bind chemical compounds by plasma proteins is poorer, and so is the blood-brain barrier permeability by low molecular weight compounds. 

In terms of ADMET, following oral administration about half of the atenolol dose is absorbed. Plasma-protein binding is minimal (3-5%). Peak plasma concentrations, as well as peak action, are reached in 2-4 h. Atenolol has low lipid solubility, and only small amounts cross the blood-brain barrier. Thus, atenolol s CNS side effects are less than with other beta-blockers [75]. Atenolol is excreted mainly by the kidneys, with little or no hepatic metabolism. It crosses the placenta, and concentrations in breast milk can be similar or even higher than those in maternal blood [76]. Atenolol is not recommended in asthma, even though its high beta-1 selectivity makes it safer in obstructive pulmonary disease than nonselective beta-blocking agents. Atenolol s important ADMET characteristics are listed in Tab. 8.2. 

Although there is no evidence that neuropsychiatric complications of macrolides develop more readily in uremic patients, several factors may predispose toward these adverse effects, such as reduced drug clearance, altered plasma protein binding, different penetration of drug across the blood-brain barrier, and an increased propensity for drug interactions. 

EXHIBIT A Anatomical and Physiological Considerations Unique to Children. differences in anatomy. allometric scaling factors (e.g. increased surface area-to-volume ratio) cardiovascular status permeability of the pediatric blood-brain barrier (BBB). dermatologic factors (e.g. increased cutaneous blood flow) (Fluhr et al., 2000 Simonen et al, 1997). increased skin pH (Fluhr et al., 2004 Behrendt and Green, 1958) plasma protein binding volume of distribution (V ) organ size and maturity pharmacokinetic maturity (e.g. metabolic differences) (Fairley and Rasmussen, 1983)... 

The ability of L-tryptophan to bind to plasma proteins of the blood and circulate as free and bound tryptophan is a unique feature for an amino acid. This binding is affected by and competes with other compounds that bind plasma proteins, such as nonesterified fatty acids (NEFA) and certain drugs. This relationship in blood affects its transport from the blood to the brain because only the free tryptophan is transplanted through the blood-brain barrier. Free tryptophan s concentration in blood in relation to other amino acids, particularly branched-chain amino acids (BCAA), affects its transport to the brain. 

The structure-activity relationship (SAR) of a compound series is a means to relate changes in chemical diversity to the biological activity of the compound / n uitro and in uiuo, as well as the pharmacokinetic (gut/blood brain barrier transit, liver metabolic stability, plasma protein binding, etc.) and toxicological properties of the molecule (119). These SARs, when known, are frequently distinct such that changes that improve the bioavailability of a compound often decrease its activity and/or selectivity. Compound optimization is thus a highly iterative and dynamic process. 

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