Oral bioavailability estimation

Fig. 19.9. G raphical oral bioavailability estimation map. (Reproduced with permission from Ref. [26] 2002 American Chemical Society.)...

Absorption - Although well absorbed orally, naltrexone is subject to significant first-pass metabolism with oral bioavailability estimates ranging from 5% to 40%. Following oral administration, naltrexone undergoes rapid and nearly complete absorption with approximately 96% of the dose absorbed from the Gl tract. Peak plasma levels of naltrexone and 6- -naltrexol occur within 1 hour of dosing. 

FIGURE 12.5 Graphical presentation for oral bioavailability estimation from in vitro data. 

Mandagere, A. K., T. N. Thompson, and K. K. Hwang. Graphical model for estimating oral bioavailability of drugs in humans and other species from their Caco-2 permeability and in vitro liver enzyme metabolic stability rates, J. Med. Chem. 2002, 45, 304-311... 

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. 

Fig. 18.7. Oral bioavailability of saquinavir with and without CFJ [42], Saquinavir (600 mg three capsules of Invirase, 200 mg each tablet) was administered to eight healthy male subjects (average body weight 76 kg) before and after consumption of two glasses (200 mL each) of CFJ at 15 and 45 min before drug administration. QMPRPIus was used to estimate human effective permeability (0.93 X 10-4 cm s 1), pure aqueous water...

In silico Models for Estimating Human Oral Bioavailability... 

Fig. 19.5. In silico model for estimating oral bioavailability. Plot of predicted versus observed bioavailability in humans for 591 drugs [22],...

It is important to remember that absolute oral bioavailability is a function of both absorption and first-pass metabolism. Therefore, a linear approach to predicting absolute oral bioavailability based on a single parameter, such as rate or extent of absorption (fraction of dose absorbed or estimated dose absorbed) or the rate of metabolism (microsomal or hepatic intrinsic clearance), may result in an inaccu-... 

This model integrates existing in vitro data, such as Caco-2 permeability (Papp) and metabolic stability in liver S9 or microsomes, to estimate bioavailability as being either low, medium, or high. Oral bioavailability predictions for not only humans but also other species can be made by using the metabolic stability values of drugs in liver microsomal enzyme preparations from that species. A premise of this model is that metabolic clearance is more important than renal or biliary clearance in determining bioavailability. However, despite the lack of in vitro renal... 

This model uses in vitro data to estimate the oral bioavailability ranges of chemically diverse compounds in a range of species, and represents a potentially powerful tool when combined with high-throughput in vitro screening. 

McCloskey, J.T., I.R. Schultz, and M.C. Newman. 1998. Estimating the oral bioavailability of methylmercury... 

An important DMPK property of a NCE is oral bioavailability (F) of the compound in various pre-clinical species.3 The oral bioavailability of a compound is dependent on several factors including intestinal permeability (estimated by the Caco-2 assay) and hepatic clearance (estimated with an in vitro metabolic stability assay).3 30 The metabolic stability assay is typically performed by incubating test compounds in liver microsomes or hepatocytes. The results can provide estimates of in vivo stability in terms of metabolic liabilities.3 8 59 62 Several authors described this assay as an important tool for the rapid assessment of the DMPK properties of NCEs.3 6 8111819 26 44 59 62-65... 

Figure 2.1 Oral drag absorption process from the gastrointestinal tract (GIT). Schematic depicting the three major processes (/a, / and /h) affecting absorption of drug from the site of administration to the systemic circulation, that is oral bioavailability, /a- fg, and /h can be estimated from the general relationship provided in Eq. 2.3 ...

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

---