First-pass elimination

W. L. Chiou, Potential pitfalls in the conventional pharmacokinetic studies Effects of the initial mixing of drug in blood and the pulmonary first-pass elimination, J. Pharmacokinet. Biopharm., 7, 527-536 (1979). 

Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A mediated metabolism, Clin. 

K., Wilkinson, G. R., Roden, D. M., Dietary salt increases first-pass elimination of oral quinidine, Clin. Pharm. Ther. 1997, 61, 292-300. 

The most important statistic represents the final plateau of the CDF and the area AUCoo of the corresponding PDF between t = 0 and t = oo. It clearly quantifies the extent of the relevant process, which is in proportion to the applied dose D, or a constant fraction or multiple f D of this, in case of overdose, chemical degradation, etc. Proportionality with dose is violated only if the process contains nonlinear or time-dependent steps such as early loss by defecation, absorption windows, chemical degradation, or non-linear presystemic (first-pass) elimination. 

Kurosaki Y, TakatoriT, KitayamaM, Nakayama T, Kimura T (1988b) Application of propranolol to the keratinized oral mucosa Avoidance of first-pass elimination and the use of 1 -dodecylazacycloheptan-2-one (Azone) as an absorption enhancer of bioadhesive film-dosage form. J Pharmacobiodyn 11 824—832... 

The two major determinants of oral bioavailability are intestinal absorption and hepatic first-pass elimination. Caco-2 cells are useful to predict intestinal absorption. The validity of this application has been demonstrated in a number of studies in which percent drug absorption in humans was correlated with Caco-2 permeability coefficients.35-39113114... 

Estrogens - Ethinyl estradiol is rapidly absorbed with peak concentrations attained in 1 to 2 hours. It undergoes considerable first-pass elimination. Mestranol is demethylated to ethinyl estradiol. Ethinyl estradiol is approximately 97% to 98% bound to plasma albumin. Half-life varies from 6 to 20 hours. It is excreted in bile and urine as conjugates, and undergoes some enterohepatic recirculation. 

Thummel KE, O Shea D, Paine MF, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Therapeut 1996 59(5) 491-502. 

Following absorption across the gut wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation. A drug can be metabolized in the gut wall (eg, by the CYP3A4 enzyme system) or even in the portal blood, but most commonly it is the liver that is responsible for metabolism before the drug reaches the systemic circulation. In addition, the liver can excrete the drug into the bile. Any of these sites can contribute to this reduction in bioavailability, and the overall process is known as first-pass elimination. The effect of first-pass hepatic elimination on bioavailability is expressed as the extraction ratio (ER) ... 

De Leede, L.G.J., et al. 1984. Site specific rectal drug administration in man with an osmotic system Influence on first-pass elimination of lidocaine. Pharm Res 1 129. 

Andersson et al. [147] studied the influence of dose on the kinetics of omeprazole and two of its metabolites, hydroxyomeprazole and the sulfone. Ten healthy subjects were given omeprazole 10 and 40 mg intravenously and 10,40, and 90 mg orally. No significant dose-related difference in parameter calculated from the intravenous experiments was detected. Following the oral solutions, there was a dose-dependent increase in the systemic availability, probably due to saturable first-pass elimination. 

For many drugs, particularly those that are substrates for CYP3A4, it is inappropriate to assume that all metabolism occurs in the liver, because intestinal enter-ocytes also contribute to first-pass elimination of these substrates (see Chap. 10). When intestinal wall metabolism contributes to the first-pass effect, the prediction of the effect of inactivation on AUCpo must be modified as follows (84) ... 

On the other hand, polycyclic aromatic compounds given orally or subcutaneously are more likely to cause aplastic anemia, leukemia, and lymphatic tumors in Ah-nonresponsive mice. These effects are manifest in tissues distant from the site of drug administration. In the example of oral benzo[a]pyrene, pharmacokinetic studies have shown a 10-and 20-fold higher uptake in the marrow and spleen of Ah-nonresponsive than of Ah-responsive mice this confirms the phenomenon called "first-pass elimination kinetics."... 

In essence, first-pass elimination kinetics means that, if a chemical administered by any route is metabolized before it reaches a target tissue, it will cause no response in that tissue. Hence, the forms of P-450 induced in the intestine and liver metabolize most of the benzo [a] pyrene given orally to the Ah-responsive mouse the amount of parent drug or its metabolites reaching the bone marrow is therefore greatly decreased. 

Efficacy can be achieved with reduced daily dosage of drug by continuing drug input and bypassing hepatic first-pass elimination. 

Eichelbaum, M., Dengler, H. J., Somogyi, A., and von Unruh, G. E. (1981). Superiority of stable isotope techniques in the assessment of the bioavailability of drugs undergoing extensive first pass elimination. Studies on the relative bioavailability of verapamil tablets. Eur. J. Clin. Pharmacol. 19, 127-131. 

The size of the polyplex is also crucial to its function. The threshold for first-pass elimination by the kidneys is approximately lOnm in diameter defining a rough lower size limit for nanoparticles (21). Upper size limits are more difficult to establish as they depend on a variety of factors that are variable within tumors including penetration of capillary endothelium, diffusion rates in tumor interstitium and intracellular spaces (22). Macromolecular complexes preferentially accumulate in tumors through the enhanced permeability and retention (EPR) effect (23). Ideally, a nanoparticle would be in a size window such that it could take advantage of the EPR effect. The size of the polyplex can be readily modified during complexation by altering the DNA to polymer ratio (24). 

---