Gut bioavailability

Major descriptive PK parameters of exposure are peak concentration (Cmax), trough concentration (Cmin), area under the plasma concentration versus time curve (AUC), and bioavailability (F) as illustrated in the time-plasma concentration profile in Figure 3.1. Primary mechanistic PK parameters contributing to the extent of drug exposure are clearance (CL) and volume of distribution (Vdss). The ratio of Vdss-to-CL is the mean residence time (MRT), an intrinsic parameter that characterizes the residence time of drug molecules in the body. CL, Vdss, and MRT can be called dispositional PK parameters as well. Fraction absorbed (/(,), gut bioavailability (Fgut), and hepatic bioavailability (Fh) are the three major mechanistic parameters that control the total bioavailability (F). 

FIGURE 3.4 Schematic illustration of the role of fraction absorbed (FJ, gut bioavailability (FgM), and liver bioavailability (Fh) in total oral bioavailability ( ). 

Amato CS, Wang RY, Wright RO, Linakis JG. Evaluation ofpromotility agents to limit the gut bioavailability of extended-release acetaminophen. J Toxicol Clin Toxicol (2004) 42, 73-7. 

First-pass metabolism is the elimination of an orally administed drug by the liver or sometimes the gut wall, before it reaches the systemic circulation. First-pass metabolism results in a decreased systemic bioavailability. 

XU X, HARRIS K s, WANG H J, MURPHY p A and HENDRicH s (1995) Bioavailability of soybean isoflavones depends upon gut microflora in women. J Nutr 125, 2307-15. 

The bioaccessibility of a compound can be defined as the result of complex processes occurring in the lumen of the gut to transfer the compound from a non-digested form into a potentially absorbable form. For carotenoids, these different processes include the disruption of the food matrix, the disruption of molecular linkage, the uptake in lipid droplets, and finally the formation and uptake in micelles. Thus, the bioaccessibility of carotenoids and other lipophilic pigments from foods can be characterized by the efficiency of their incorporation into the micellar fraction in the gut. The fate of a compound from its presence in food to its absorbable form is affected by many factors that must be known in order to understand and predict the efficiency of a compound s bioaccessibility and bioavailability from a certain meal. ... 

A number of factors described as influencing carotenoid bioavailability were regrouped under the SLAMENGFll mnemonic. Species of carotenoid. Linkages at molecular level. Amount of carotenoids consumed in a meal. Matrix in which the carotenoid is incorporated. Effectors of absorption and bioconversion. Nutrient status of the host. Genetic factors. Host-related factors, and Interactions among these variables. Only the factors that affect the micellarization of the compound in the gut are discussed and summarized in Table 3.2.1. 

The degree of linkage of a compound may also affect its bioaccessibility in the gut. It is generally admitted that a compound linked with other molecules (e.g., via esterification, glycosylation, etc.) is not absorbed as well as its free form and thus it must be hydrolyzed in the gut in order to be taken up by enterocytes. Due to the presence of hydroxyl or keto groups on their molecules, the xanthophylls (lutein, zeaxanthin, and P-cryptoxanthin) are found in both free and esterified (monoester or diester) forms in nature, but few studies have been conducted to date to assess the bioavailabilities of these esters. 

The AUC is a measure of bioavailability, i.e. the amount of substance in the central compartment that is available to the organism. It takes a maximal value under intravenous administration, and is usually less after oral administration or parenteral injection (such as under the skin or in muscle). In the latter cases, losses occur in the gut and at the injection sites. The definition also shows that for a constant dose D, the area under the curve varies inversely with the rate of elimination kp and with the volume of distribution V. Figure 39.6 illustrates schematically the different cases that can be obtained by varying the volume of distribution Vp and the rate of elimination k both on linear and semilogarithmic diagrams. These diagrams show that the slope (time course) of the curves are governed by the rate of elimination and that elevation (amplitude) of the curve is determined by the volume of distribution. 

The fraction of the orally administered dose that is bioavailable to the systemic circulation (Fsystemjc) is dependent upon the fraction of the dose that is released from the dosage form (/released), multiplied by the fraction that is absorbed into the portal circulation on its way to the liver (/absorbed this is the fraction that escapes gut metabolism), multiplied by the fraction of the dose that escapes the hepatic first-pass effect (/hepatic)- Since this is a multiplicative process if, for... 

For this calculation, it is unnecessary to assume that Vd and/or kei are the same for the two studies. It is only necessary that fe be the same in both studies. This is usually a valid assumption unless the drug undergoes a significant amount of first-pass metabolism in the gut wall or liver following oral administration or a significant amount of decomposition at an intra muscular (IM) injection site. When this occurs, the availability of the extravascular dosage form may appear to be low, but the fault will not lie with the formulation. The bioavailability will be a true reflection of the therapeutic efficacy of the drug product, and reformulation may not increase bioavailability. 

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] ... 

A direct in vivo assessment of the quantitative importance of gut wall metabolism and transport of drugs and metabolites in humans is difficult and consequently has been attempted only rarely [3, 6, 11, 12, 15, 16, 23, 25-32, 34, 35, 81]. The most direct in vivo approach to investigating these processes in drugs with variable and incomplete bioavailability was intestinal perfusion by single-pass per-... 

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. 

I 73 The Importance of Gut Wall Metabolism in Determining Drug Bioavailability... 

The midazolam example shows that gut wall cytochrome P450 can contribute significantly to the attenuation of oral bioavailability of substrate drugs. In addition, the variability and site dependence of expression of the major intestinal CYPs can lead to significant effects on the disposition of orally delivered drugs. 

Wacher et al. [31] have shown that, in contrast to CYP3A4, P-gp mRNA levels increase longitudinally along the intestine (lowest levels in the stomach and highest in the colon). Lown et al. [32] have shown using duodenal mucosal biopsies (n = 20) that there was a 10-fold variation in the P-gp mRNA level, suggesting that there will be variability in the expression of P-gp in the gut and this will lead to potential variability in oral bioavailability. 

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

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. 

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