The plasma protein binding of drugs has been shown to have significant effects on numerous aspects of clinical pharmacokinetics and pharmacodynamics. In many clinical situations, measurement of the total drug concentration does not provide the needed information concerning the unbound fraction of drug in plasma which is available for distribution, elimination, and pharmacodynamic action. Thus, accurate determination of unbound plasma drug concentrations is essential in the therapeutic monitoring of drugs. Many methodologies are available for determining the extent of plasma protein binding of drugs, however, in the clinical evaluation of drug therapy, equilibrium dialysis and ultrafiltration are the most routinely utilised methods. Both of these methods have been proven to be experimentally sound and to yield adequate protein binding data. Furthermore, the characterisation of the interactions between drug and protein molecules is essential for the assessment of the pharmacokinetic implications of drug-protein binding. Protein binding parameters which characterise the affinity of the drug-protein association, the number of classes of binding sites, the number of binding sites per class or protein and the binding capacity are useful for predicting unbound drug concentrations. Simple graphical methods have often been used to obtain protein binding parameters, but these methods have limitations and are not useful for drugs with more than 1 class of binding site. Therefore, the fitting of protein binding models which characterise the drug-protein binding interaction for experimental data is the preferred method of calculating binding parameters. Using the appropriate model, values for binding parameters are typically estimated by using nonlinear least-squares regression analysis.

The plasma protein binding of drugs, particularly those that are highly bound, may have significant clinical implications. Although protein binding is a major determinant of drug action, it is only one of a myriad of factors that influence drug disposition. The extent of protein binding is a function of drug and protein concentrations, the affinity constant for the drug-protein interaction and the number of protein binding sites per class of binding site. Age-related changes in protein binding are usually not clinically important in drug therapy. Albumin levels are generally decreased in the elderly, whereas alpha1-acid glycoprotein levels are not altered by age per se. Alterations in plasma protein binding that occur in the elderly are generally not attributed to age, but rather to physiological and pathophysiological changes or disease states that may occur more frequently in the elderly and most often account for altered protein binding. Age-related physiological changes, such as decreased renal function, decreased hepatic function and decreased cardiac output, generally produce more clinically significant alterations in drug disposition than that seen with alterations in drug plasma protein binding. An understanding of the inter-relationships between drug concentrations, protein binding, the physiology of aging, disease, pharmacokinetics and pharmacodynamics is necessary for effective therapeutic monitoring. Monitoring of unbound drug concentrations simplifies these relationships and provides the fundamental information needed for dosage regimen development and adjustment. Drug therapy in the elderly should be individualised taking into account all of these factors.

Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Ab) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Ab production has not been ruled out. We show that ibuprofen reduced Ab brain levels in rats from exogenously infused Ab in the absence of altered Ab production. To determine whether ibuprofen inhibits proamyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Ab and inflammation-related molecules a 1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor g) (PPARg) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1b, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Ab42 production, these observations suggest that ibuprofen reduction of Ab pathology may not be mediated by altered Ab42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1b and its downstream target ACT).

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Fullerenes are the recently discovered third allotropic form of carbon. The biological activities of these compounds are being studied for various purposes. The bis(monosuccinimide) derivative of p p'-bis(2-amino-ethyl)-diphenyl-C60 (MSAD-C60) is a water-soluble fullerene derivative. MSAD-C60 has been shown to have antiviral activity against human immunodeficiency virus types 1 and 2 in vitro and to have virucidal and anti-human immunodeficiency virus protease activities. Moreover, MSAD-C60 has been shown to be well tolerated in mice after intraperitoneal administration. The purpose of the present study was to develop a high-performance liquid chromatographic analytical methodology for MSAD-C60 and to characterize the preclinical pharmacokinetics of the compound in rats. Following intravenous administration of the fullerene derivative at a dose of 15 mg/kg of body weight, the concentrations of MSAD-C60 in plasma declined either bi- or triexponentially. The mean terminal-phase half-life of MSAD-C60 was 6.8 +/- 1.1 h (mean +/- standard deviation). Binding studies indicated that the compound is greater than 99% bound to plasma proteins. The average total clearance of the compound was 0.19 +/- 0.06 liter/h/kg. Urine samples obtained 24 h after intravenous administration did not contain detectable levels of the compound, indicating the absence of a significant renal clearance mechanism. The steady-state volume of distribution of MSAD-C60 averaged 2.1 +/- 0.8 liters/kg, indicating that the compound distributes into tissues. At a dose of 15 mg/kg, MSAD-C60 appeared to be well tolerated. However, a dose of 25 mg/kg resulted in shortness of breath and violent movement of the rats, followed by death within 5 min of dosing. Further controlled toxicity studies are needed to fully evaluate the toxicity of the compound.

nucleoside analogs which inhibit human and simian immunodeficiency virus in vitro. The pharmacokinetic properties of these compounds in rhesus monkeys after intravenous, oral, and subcutaneous administration of the drug were compared. Half-lives, total clearances, and steady-state volumes of distribution for the two drugs were determined. The half-lives for the drugs by the different routes were between 0.58 and 1.4 h. Oral bioavailabllity of 3'-deoxy-2',3'-didehydrothymidine was incomplete, with an average of 42% ± 15% of the dose reaching the systemic circulation. Absorption of 3'-fluoro-3'-deoxythymidine after oral administration was variable, with bioavailability ranging from 21 to 95%. Bioavailability after subcutaneous administration ranged from 59 to 77% for 3'-deoxy-2',3'-didehydrothymidine and from 52 to 59% for 3'-fluoro-3'-deoxythymidine. The ratio of concentrations in cerebrospinal fluid and serum for the drugs was about 0.15 at 1 h after drug administration and was independent of the route of administration, suggesting that a nucleoside carrier-mediated process is involved in the transport of these compounds to the central nervous system. Because of the similar metabolism of nucleoside analogs in monkeys and humans, the potential glucuronide formation was assessed. Whereas the glucuronide of 3'-fluoro-3'-deoxythymidine was readily detected in urine, the amount of 3'-deoxy-2',3'-didehydrothymidine glucuronidated was small or not detectable in one-half of the urine samples. Pharmacokinetic parameters for the two drugs were similar to each other and analogous to those for 3'-azido-3'-deoxythynidine in monkeys, suggesting that the same dose and scheduling of the drug can be used for all three compounds in prophylactic and therapeutic efficacy drug studies in rhesus monkeys.

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