Correlation of Oral Drug Bioavailability and Intestinal Permeability Between Rat and Human

Animal models are widely used to evaluate drug pharmacokinetics and drug absorption. However, the correlation of oral bioavailability (F) values of 48 drugs in rat and human has been studied and no correlation (r2 = 0.29) was found due to low correlation of drug metabolism in rat and human (Cao et al., 2006). Results of the F values comparison are shown in Fig. 4.14. In contrast, Chiou and Buehler observed low correlation in the bioavailability of 35 drugs between monkey and human with r2 = 0.502 (Chiou and Buehler, 2002), which may be due to the closer physiological similarity between monkey and human. These data indicate that oral bioavailability in rat could not be used to predict oral drug bioavailability in human.

Due to the structural similarities of intestinal membrane, drug absorption in animal models may be used to predict drug absorption in human. In order to depict the oral drug absorption process, in situ intestinal permeabilities of 17 drugs with different absorption mechanisms were evaluated in rat and human jejunum (Cao et al., 2006). Since permeability is one of the primary factors governing absorption (Amidon et al., 1995), studying the permeability correlation is useful when predicting human absorption from rat permeability. The tested drugs are absorbed by carrier-mediated processes as well as passive diffusion. For instance, valacyclovir, enalapril, and cephalexin are all absorbed through a peptide transporter (hPepT1). Leucine, phenylalanine, L-Dopa, and methyldopa are absorbed through amino acid transporters. Verapamil is a P-gp substrate. Cimetidine is an organic cation transporter substrate. Propranolol, atenolol, and furosemide are all absorbed through passive diffusion. The drug permeabilities in the rat jejunum were then correlated

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= 0.5918Frat + 37.358 R2 = 0.2917

Oral Bioavailability in Rat (%)

Figure 4.14. Correlation of oral bioavailability between rat and human. Total of 48 drugs were plotted. The equation describes the correlations for rat oral bioavailability (Frat) and human oral bioavailability (Fhuman) (Cao et al., 2006)

Log P_ = 1-28 log Prat + 2.064, R2 = 0.7 LogPhuman = 1.34 logPrat + 1.83, R2 = 0.8 (without verapamil)

A Phenylalanine O L-Dopa

X Valacyclovir Zi Enalapril U Cephalexin 63 Methyldopa □ Propranolol o Cimetidine • Atenolol

0.01

Log P_ = 1-28 log Prat + 2.064, R2 = 0.7 LogPhuman = 1.34 logPrat + 1.83, R2 = 0.8 (without verapamil)

▲ Furosemide X Ketoprofen + Naproxen + Antipyrine A Metoprolol

0.01

0.1 1 Intestinal Permeability in Rat (x 10-4 cm/s)

10 O Tacrolimus

Figure 4.15. Correlation of drug permeability in rat jejunum and in human jejunum. Permeability coefficients (Peff) were determined by in situ intestinal perfusion. The equations describe the correlations for rat permeability (Prat) and human permeability (Phuman) (Cao etal., 2006)

with the drug permeabilities in the human jejunum (Fig. 4.15). It showed that drug permeability in the rat is generally five to ten-fold lower than the permeability in the human. However, both carrier-mediated and passively diffusing drugs showed a reasonable correlation (r2 = 0.7). Interestingly, verapamil (a P-gp substrate) permeability in human deviates from the correlation curve. The permeability correlation between human and rat is highly increased (r2 = 0.8) when verapamil is excluded in the analysis.

This study is in agreement with the other report, that the percentage of absorption of 98 drugs was correlated between rat and human with a correlation of r2 = 0.88 (Zhao et al., 2003). In vivo absorption in rats could be a useful method to predict the extent of absorption in humans. The permeability in rat for water soluble and poor water soluble compounds was used to predict the fraction of drug absorbed in humans (Watanabe et al., 2004). In another study, a high correlation was found for a variety of compounds displaying various physicochemical and pharmacologic activities between the two species in the dose-independent absorption range (Chiou and Barve, 1998). However, a previous study reported that effective permeability estimates of passively absorbed solutes correlate highly in rat and human jejunum while carrier-mediated transport requires scaling between the models because the substrate specificity and/or transport maximum may differ (Fagerholm et al., 1996). These discrepancies might be due to the different numbers of transporter substrates that are used in the correlation analysis. However, all of these studies indicate that reasonable permeability correlation between human and rat can be used to predict drug absorption in humans.

To understand the underlying mechanisms in the similarity in drug intestinal absorption between humans and rats, correlation analysis of the expression levels of transporters and metabolizing enzymes between rat and human intestine were further conducted (Cao et al., 2006). Moderate correlations (with r2 > 0.56) were found for the expression levels of transporters in the duodenum of human and rat. Although there is discrepancy observed in the expression of MDR1, MRP3, GLUT1, and GLUT3, other transporters (such as PepTl, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) and the overall drug transporters expression share similar expression levels in both human and rat intestine with regional dependent expression patterns, which has high expression in the small intestine and low expression in the colon. These data provide the molecular mechanisms for the similarity and correlation of drug absorption (Fa) in the small intestine between rat and human. In contrast, the expression of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12- to 193fold difference between human and rat intestine with distinct regional dependent expression patterns. No correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicate the difference in drug metabolism in two different species and the challenges in predicting Fg and F from rat to human.

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