First-pass extraction

A special case for reduced bioavailabilty results from first-pass extraction that sometimes might be subjected to saturable Michaelis-Menten absorption kinetics. The lower the hepatic drug clearance is (Clhep) in relation to liver blood flow (Ql), or the faster the drug absorption rate constant (Ka), and the higher the dose (D) are, the more bioavailable is the drug (F). 

SD Hall, KE Thummel, PB Watkins, KS Lown, LZ Benet, MF Paine, RR Mayo, DK Turgeon, DG Bailey, RJ Fontana, SA Wrighton. Molecular and physical mecahnisms of first-pass extraction. Drug Metab Dispos 27 161-166, 1999. 

The most useful pharmacokinetic variable for describing the quantitative aspects of all processes influencing the absorption (fa) and first-pass metabolism and excretion (Eg and Eh) in the gut and liver is the absolute bioavailability (F) [40]. This pharmacokinetic parameter is used to illustrate the fraction of the dose that reaches the systemic circulation, and relate it to pharmacological and safety effects for oral pharmaceutical products in various clinical situations. The bioavailability is dependent on three major factors the fraction dose absorbed (fa) and the first-pass extraction of the drug in the gut wall (EG) and/or the liver (EH) (Eq. (1)) [2-4, 15, 35] ... 

Fraction escaping gut wall first-pass extraction... 

The mesenteric blood empties into the hepatic portal vein from where it is transported to the liver. At the liver, drug and metabolites can also be extracted from the portal blood and either metabolized or excreted unchanged into the bile. This is termed hepatic first-pass extraction. 

Thus, the oral bioavailability of a drug is determined by the amount absorbed from the GIT, the fraction escaping first-pass extraction by the gut, and the fraction escaping first-pass extraction by the liver. It is summarized by the following equation ... 

Consequently, the gut wall can exert a significant outcome on the overall oral bioavailability of a drug molecule. It is now time to consider the enzymes and transporters, which combine to express gut wall first-pass extraction. 

Overall, the human intestine is capable of metabolizing UDP-glucuronyltransferase substrates, although the rates of metabolism are between 5- and 10-fold lower than those observed in human liver microsomes. However, the presence of a metabolic capacity towards UDP-glucuronyltransferase substrates at the level of the enterocyte can exert a significant gut wall first-pass extraction on oral administration. 

These enzymes (and transporters) exhibit differential expression at various sites throughout the GIT. For example, CYP3A4 expression is highest in the duodenum and lowest in the colon conversely, the expression of P-gp is greatest in the colon. This has implications for the gut wall first-pass extraction of drugs delivered by modified-release formulations, where the majority of the drug must be absorbed from the colon. 

The expression of metabolic enzymes in the enterocyte can lead to a profound gut wall first-pass extraction ratio for substrate drugs. In addition, efflux transporters can slow the passage of drugs across the enterocyte in a cycling fashion. This allows the metabolic enzymes several opportunities to metabolize their substrates, and in this way a low expression level of an enzyme can exhibit a significant extraction. 

The expression of a significant gut wall first-pass extraction ratio has several implications for affected drugs. First, oral bioavailability is lower than would be expected from the extent of absorption and the hepatic first-pass extraction. Second, the variability in expression of gut wall metabolic enzymes and transporters can lead to significant variability in gut wall first-pass extraction and thus oral bioavailability. Finally, the site of expression of these enzymes and transporters (i.e., the villus tip) brings them into contact with potentially co-administered drugs or dietary constituents, which could be inhibitors or inducers. Thus, there is the potential for drug-drug interactions at the level of the gut wall. 

Unchanged passive diffusion and no change in bioavailability for most drugs l Active transport and i bioavailability for some drugs l First-pass extraction and T bioavailability for some drugs i Volume of distribution and T plasma concentration of water-soluble drugs T Volume of distribution and T terminal disposition half-life (t ) for fat-soluble drugs... 

Hall SD, Thummel KE, Watkins PB, Lown KS, Benet LZ, Paine MF, Mayo RR, Turgeon DK, Bailey DG, Fontana RJ, Wrighton SA (1999) Molecular and physical mechanisms of first-pass extraction. Drug Metab Dispos 27(2) 161—166. 

M. Koike, S. Futaguchi, S. Takahashi, K. Sugeno, Biopharmaceutical Characterization of 450191-S, a Ring-Opened Derivative of 1,4-Benzodiazepine. II. Evidence for Reduced First-Pass Extraction by Rat Liver , Drug Metab. Dispos. 1988, 16, 609-615. 

This postulated phenomenon can have the beneficial effect of reducing the likelihood of systemic side-effects by effectively buffering the rate at which the drag enters the systemic circulation and hence reducing peak-to-trough variations in concentration. Conversely, high affinity for Hver Hssue may increase exposure to the enzymes of clearance and may therefore attenuate the first-pass extraction of drugs. 

Because of their low molecular weight (<2000 Da), the standard NS-CA are extravasated to a massive extent on first pass in noncerebral areas. Thus, Canty et al. reported that first-pass extraction of a conventional nonionic CA averaged 33 % in normally perfused myocardial areas and 50% in stenotic areas (where coronary blood flow was reduced by 50%) [15]. These data may even have underestimated first-pass myocardial extraction of CA because of back diffusion of the molecule. In another model, approximately 80% of the myocardial content of I-iothalamate was found in the extravascular space 1 minute after intravenous injection in rats [16]. 

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lactones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A), Atorvastatin has the longest duration of action. 

PET offers the possibility to quantitatively measure the myocardial blood flow (MBF). MBF tracers can be divided into two groups. The first group is freely diffusible and represented by [ 0]H20. These tracers do not show any specific absorption and their distribution is completely determined by diffusion. Consequently, the measurement of the MBF is based on the first-pass extraction and clearance data. Because of the low heart-to-blood radioactivity ratio, the freely diffusible tracers provide myocardial images with low signal-to-background ratios. The second class is composed of highly extractable heart tracers. The tracer p NjNHs belongs to this family. These radiolabeled compounds are characterized by a selective extraction and retention in the myocardium. The... 

Considerable research has been directed toward understanding the effect of potent CYP3A inhibitors on the first-pass extraction of drugs at both the... 

The extent to which P-gp activity influences intestinal CYP3A-mediated first-pass extraction in vivo is still unclear. However, Johnson et al. (148) did show that selective inhibition of P-gp mediated verapamil efflux with PSC833 reduced the extent of intestinal first-pass metabolism in an autoperfused rat... 

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