Disease plasma protein binding

AED pharmacokinetic data are summarized in Table 52-3. For populations known to have altered plasma protein binding, free rather than total serum concentrations should be measured if the AED is highly protein bound. Conditions altering AED protein binding include chronic renal failure, liver disease, hypoalbuminemia, burns, pregnancy, malnutrition, displac-... 

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). 

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. 

Some disease states (e.g., hyperalbuminemia, hy-poalbuminemia, uremia, hyperbilirubinemia) have been associated with changes in plasma protein binding of drugs. For example, in uremic patients the plasma protein binding of certain acidic drugs (e.g., penicillin, sulfonamides, salicylates, and barbiturates) is reduced. 

It is important to note that the elimination half-life is a derived term, and any process that changes k will change the half-life of the drug. Factors that may affect pharmacokinetic parameters are discussed elsewhere, but in this example may include disease states, changes in urinary pH, changes in plasma protein binding, and coadministration of other drugs. 

Renal diseases such as uremia may result in decreased renal clearance of certain drugs.13 Gastrointestinal diseases, such as Crohn s disease, result in increased plasma protein binding of several drugs due to increased levels of binding proteins. Further, respiratory diseases such as cystic fibrosis increase the renal clearance of some drugs. 

Powell LW, Axelsen E. Corticosteroids in liver disease studies on the biological conversion of prednisone to prednisolone and plasma protein binding. Gut 1972 13(9) 690-6. 

Neuraminidase is an essential viral glycoprotein for virus replication and release. The neuraminidase inhibitors zanamivir and oseltamivir have recently been approved for the treatment of acute uncomplicated influenza infection. When a 5-day course of therapy is initiated within 36-48 hours after the onset of symptoms, use of either agent shortens the severity and duration of illness and may decrease the incidence of respiratory complications in children and adults. Unlike amantadine and rimantidine, zanamivir and oseltamivir have activity against both influenza A and influenza B. Zanamivir is administered via oral inhaler. The compound displays poor oral bioavailability, limited plasma protein binding, rapid renal clearance, and absence of significant metabolism. Nasal and throat discomfort may occur—as well as bronchospasm in patients with reactive airway disease. 

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. 

Grainger-Rousseau TJ, McElnay JC, Collier PS (1989) The influence of disease on plasma protein binding on drugs. International Journal of Pharmaceutics 54 1-13... 

As bound concentration falls, the free concentration is more available for distribution and elimination, and as total concentrations are therefore lower, hypoalbuminaemia can lead to an increase in apparent volume of distribution. However, tissue distribution may also change in hepatic disease. This is illustrated by tolbutamide in viral hepatitis. No change was found in the volume of distribution of tolbutamide because changes in plasma protein binding were matched by changes in tissue binding [9]. 

VI. EFFECT OF DISEASE STATE ON ENANTIOSELECTIVE PLASMA PROTEIN BINDING... 

The vast majority of studies on drug-protein binding have employed solutions of isolated plasma proteins or serum samples from healthy volunteers. Few data are currently available on the potential of enantio-selective disease-induced changes in plasma protein binding. This is the... 

Tozer, T.N. Implications of altered plasma protein binding in disease states. In Pharmacokinetic Basis for Drug Treatment, Benet, L.Z., Massoud, N., Gambertogho, J.G., Eds. Raven Press New York, 1984 173-193. 

Lohman JJ, Merkus FW. Plasma protein binding of digitoxin and some other drugs in renal disease. Pharm Weekbl Sci 1987 9(2) 75-8. 

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