Naproxen distribution

While many aspects of nonlinear pharmacokinetic behavior may impact on the above equation, the more relevant pharmacokinetic processes for ASOs are absorption and distribution at or below therapeutic or nontoxic plasma concentrations. Nonlinear absorption or distribution processes can affect AUC terms in a nonproportional manner when different doses are compared, thereby resulting in an inaccurate determination of bioavailability. This has been shown to occur on numerous occasions for compounds such as ascorbic acid or naproxen [59-62]. Such cases require an understanding of the capacity-limiting cause of the nonlinearity and the pharmacokinetic processes upon which this impacts, in case of ASOs absorption and intercompartmental distribution processes from the central compartment into the peripheral tissues. With this understanding, various methods may then be applied to best approximate the rate of change of the plasma concentrations from one sampling time to the next allowing for an estimate of the absolute BAV. 

The 2-arylpropionic acid ( profen ) non-steroidal anti-inflammatory drugs, each of which contains a single chiral center, are formulated as racemic (50 50) mixtures of the S(+)- and R(-)-enantiomers, with the exception of naproxen, which is formulated as the S(- -)-enantiomer. Based on inhibition of cyclooxygenase activity, the S(- -)-enantiomer is the eutomer (more potent enantiomer). These drugs differ markedly in both pharmacodynamic activity and pharmacokinetic behavior and, in addition, enantiomer pharmacokinetics of each drug varies among animal species. After intravenous administration of racemic keto-profen to horses, sheep, and 20-week-old calves and measurement of individual enantiomers in plasma, significant differences between the enantiomers were found in systemic clearance in horses and in both systemic clearance and volume of distribution in sheep... 

Renal disease (uraemia) may increase the volume of distribution of acidic drugs that extensively bind to plasma albumin (e.g., phenytoin, valproic acid, naproxen, phenylbutazone, furosemide). As decreased protein binding would increase the unbound (free) fraction in the plasma, the therapeutic concentration range (based on total drug concentration) would be lower than the usual... 

Unger SH, Cook JR and Hollenberg JS, Simple procedure for determining octanol-aqueous partition, distribution, and ionization coefficients by reversed phase high pressure liquid chromatography, /. Pharm. Sci, 67 1364-1367 (1978). NB See Naproxen for details. 

The pFI used in studying buprofen was not refrorted. We assumed a pFI of 3.0, which is the same pFI at which penetration of the other carboxylic adds (indomethacin, ketoprofen, naproxen) and the distribution coefficients were measured. 

C. Pharmacokinetics. NSAIDs are generally well absorbed, and volumes of distribution (Vd) are relatively small (eg, 0.15 L/kg for ibuprofen). COX-2 inhibitors have larger volumes of distribution (86-91 L in adults for rofecoxib, 400 L for celecoxib). Most agents are highly protein bound, and most are eliminated through hepatic metabolism and renal excretion with variable half-lives (eg, 1.5-2.5 hours for ibuprofen and 12-17 hours for naproxen). (See also Table 11-59.)... 

The apparent volume of distribution of naproxen averaged abut 8.3 L in healthy adults and about 11.9 L in patients with severe renal failure (serum creatinine 5.4-12.5 mg/dl)(2). In healthy adults, plasma half-life of naproxen reporfly ranges from 10-20 hours. 

Distribution naproxen has a volume of distribution of 0.16 L/kg. The elimination half-life of naproxen is approximately 15 hours following normal therapeutic doses. Naproxen is almost completely (99%) boimd to albumin and other plasma proteins. It crosses the placenta and appears in the milk of lactating women at approximately 1% of the plasma level concentration. Substantial amounts are found in the spinal fluid [1-3]. 

Figure 12 Particle size distribution of naproxen granulations milled using hand screen and Comil.

By employing, the semiempirical quantum mechanical method AMI, the molecular geometries of the arylalkanoic acids, indomethacin, naproxen, and ibuprofen, were optimized and their frontier orbital charge distributions assessed. Afterward, these molecular parameters were matched in order to recognize structure-activity relationships. Bearing in mind these evaluations. 

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