Oral pharmacokinetics

Nelfinavir. Using structure-based design in conjunction with predicted oral pharmacokinetics, NFV was identified and found to have potent inhibition of HIV-1 in vitro with an IC50 in the 2nM range (Kaldor et al. 1997). Clinical trials of NFV revealed robust and sustained reductions in HIV-1 RNA with over half of all subjects attaining a persistent 1.6 logxo reduction at 12 months, in conjunction with a mean increase in CD4 cells of 180-200 per mm (Markowitz et al. 1998). In subjects... 

Fig. 14.12 VolSurf model to correlate 49 matrix metalloproteinase inhibitors with different zinc-binding functionalities to rabbit oral bioavailability for metabolically stable compounds. (A) Semiquantitative PLS model 0.424, r 0.646, 4 PLS components) to rank novel synthesis candidates. Main factors influencing absorption, that is, lower polarity, capacity factors and increased hydrophobicity, are in agreement with global models for human intestinal absorption. (B) Distribution of polar and hydrophobic surfaces for two molecules with low (0981) and higher (2290) rabbit AUC from oral pharmacokinetic studies.

In this project, compound A from a potential lead series was a neutral compound of MW 314 with low aqueous solubility (Systemic clearance, volume and AUC following a 0.5mg/kg intravenous dose to rats were well predicted (within twofold) from scaled microsomal clearance and in silica prediction of pKa, logP and unbound fraction in plasma. Figure 10.3a shows the predicted oral profile compared to the observed data from two rats dosed orally at 2mg/kg. The additional inputs for the oral prediction were the Caco-2 permeability and measured human fed-state simulated intestinal fluid (FeSSIF, 92(tg/mL). The oral pharmacokinetic parameters Tmax. Cmax. AUC and bioavailability were well predicted. Simulation of higher doses of compound A predicted absorption-limited... 

The therapeutic outcome of topically applied agents used to control oral infections will depend on the characteristics of drugs that take advantage of the unique physiological and anatomical circumstances in the oral cavity. This section is a broad overview of important oral pharmacokinetic principles. 

Allen, M. C. Shah, T. S. Day, W. W. 1998. Rapid determination of oral pharmacokinetics and plasma free fraction using cocktail approaches methods and application. Pharm. Res., 15, 93-97. 

Yamazaki S et al (2011) Prediction of oral pharmacokinetics of cMet kinase inhibitors in humans physiologically based pharmacokinetic model versus traditional one-compartment model. Drug Metab Dispos 39 383-393... 

The difficulty in determining dose delivered with oral administration of high-dose busulfan in preparative regimens for hematopoietic stem cell transplantation results in lethal toxicity due to overdosing and increased potential for relapse with recurrent disease. Oral pharmacokinetic studies ineffectively determine proper AUC for reliable establishment for a proper therapeutic dose. Studies with IV formulations have demonstrated that all patients are evaluable. With the development of a limited sampling strategy to analyze proper AUC over intermittent time periods, improved patient risk profiles for busulfan have been implemented in clinical practice. 

M Eichelbaum, A Somogyi, GE von Unruh, HJ Dengler. Simultaneous determination of the i.v. and oral pharmacokinetic parameters of D,L-verapamil using stable labelled verapamil. Eur J Clin Pharmacol 19 133—137, 1981. 

Stewart B, Wang Y, Surendran N. Ex. In vivo approaches to predicting oral pharmacokinetics in humans. In Ann Repts Med Chem. Trauma, 6 ed. Academic Press, 2000 35 299-307. 

Feng, M. R. et al., Allometric pharmacokinetic scaling towards the prediction of human oral pharmacokinetics, Pharm. Res., 17 410-418, 2000. 

TABLE 5.5 Percent reduction in oral pharmacokinetic parameters due to enzyme induction by rifampicin or St. John s wort. 

Yu KS, Cho JY, Shon JH, Bae KS, Yi SY, Lim HS, Jang IJ, Shin SG. Ethnic differences and relationships in the oral pharmacokinetics of nifedipine and erythromycin. Clin Pharmacol Ther 2001 70 228-236. 

The pharmacokinetics of clinafloxadn are nonstereoselective in human volunteers after both oral and intravenous doses (Table 2) [8]. Similarly, the oral pharmacokinetics of tosufloxadn are also nonstereoselective with respect to serum tjnoK, ty, and AUC (Table 1). However, the renal clearance of the (—) enantiomer is significantly higher (12%) than that of the (-I-) enantiomer [7]. 

Koneru B, Bramer S, Bricmont P, Maroli A, Shiba K. Effect of food, gastric pH and co-administration of antacid, dmetidine and probenecid on the oral pharmacokinetics of the broad spectrum antimicrobial agent grepafloxacin. Pharm Res (1996) 13 (9 Suppl), S414. 

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