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to a greater extent in man.

With regard to interspecies differences in secretions into the intestinal tract, an important anatomical difference between rats and humans is the absence of a gall bladder in rats. This means that in the rat, bile enters the duodenum continuously as it is made. By contrast the bile in humans is released only when chyme is present. These anatomical differences can be responsible for pronounced species differences in the concentration versus time profile of drugs that undergo enterohepatic recycling.

There are also some important similarities and differences in gastrointestinal physiology40-42 between dogs and humans, which are discussed below. The physiology of the stomach is relatively similar under fasting conditions in both dog and man. The higher intestinal pH observed in the dog is the main difference between the species under fasting conditions. This could lead to species differences in the absorption of compounds for which solubility is a function of pH in the region of 5-7 and for enteric-coated formulations with dissolution in this pH range. Dogs also exhibit short intestinal transit time, which could lead to lower absorption for compounds slowly absorbed in the colon and for compounds in slow-release dosage forms. Postprandially, differences occur in both the gastric and intestinal physiology. For example, meal emptying rates are much slower in the dog. Furthermore, gastric and intestinal pH appears to be more acidic in dogs than in humans. These lower pH values may result in different absorption rates between dog and man for compounds whose intestinal permeability or solubility are affected by fraction ionized. These species differences in physiology between fasted and fed state might also result in different food effects on pharmacokinetics between human and dog.

Solubilization of lipophilic drugs is a critical step in ensuring its bioavailability. This solubilization process is highly dependent upon the presence and nature of the bile salts contained within the intestinal fluids. However, the marked interspecies differences in bile flow and composition can significantly affect the nature of this solubilization process.

The solubility of poorly soluble compounds was recently compared in dog and humans. For danazol, felodipine, and griseofulvin, the solubility in dog intestinal fluid was significantly higher than in human intestinal fluid, indicating that dog might not be a suitable species to predict human absorption for these poorly soluble compounds.43 This higher solubility in dog intestinal fluid reflects the influence of higher bile salt concentration in dog as compared to man.

5.03.6.1.2 Interspecies comparison of fraction absorbed

Despite the differences in physiology, nearly identical oral absorptions in humans and rats have been reported for 64 drugs with markedly varying physicochemical properties and a wide range of intestinal permeabilities (Figure 6).38

In addition, similar oral bioavailabilities in rats and humans have been reported for 16 PEG compounds with molecular weights ranging from 280 to 950.44

The monkey may be another excellent animal model for predicting oral absorption in humans.35 Chiou and Buehler found that absorption values in monkeys were similar or identical to those in humans (Figure 7). In contrast to rat and monkey, the dog appears to be less predictive for man. In general there is a tendency for dogs to absorb compounds

Figure 6 Oral absorption in rat versus human of 64 drugs with markedly different physicochemical properties. (Reproduced from Chiou, W. L.; Barve, A. Pharm. Res. 1998, 15, 1792-1795.38)

Figure 6 Oral absorption in rat versus human of 64 drugs with markedly different physicochemical properties. (Reproduced from Chiou, W. L.; Barve, A. Pharm. Res. 1998, 15, 1792-1795.38)

0 20 40 60 80 100 Human absorption (A%)

Figure 7 Oral absorption in cynomolgus monkey versus human of 43 drugs with markedly different physicochemical properties. (Reproduced from Chiou, W. L.; Buehler, P. W. Pharm. Res. 2002, 19, 868-874.35)

0 20 40 60 80 100 Human absorption (A%)

Figure 7 Oral absorption in cynomolgus monkey versus human of 43 drugs with markedly different physicochemical properties. (Reproduced from Chiou, W. L.; Buehler, P. W. Pharm. Res. 2002, 19, 868-874.35)

better than man. For the 16 PEG compounds the absorption in dogs was better than in humans.44 Also for 43 drugs, the correlation coefficient between the fraction absorbed in humans and dogs (r2 = 0.51) was much lower than that (r2 = 0.97) reported between humans and rats36,38 (Figure 8).

For acyclovir and nadolol, the fraction absorbed in dogs was about 100% while humans only absorbed about 20% of the dose. Great differences were also found for atenolol (50% in man versus 100% in dogs), methyldopa (43% in man versus 100% in dogs), ranitidine (63% in man versus 100% in dogs), sumatriptan (60% in man versus 97% in dogs), and xamoterol (8.6% in man versus 36% in dogs).

A number of hypotheses have been proposed to explain the higher absorption in dog as compared to man. For example, the dog has longer villi, which may compensate for a shorter intestinal transit time. Furthermore, the higher bile salt secretion rate in the dog could increase the permeability of the intestinal membrane and might, through a solubilizing effect, also facilitate the absorption of poorly water-soluble drugs.36,38 In addition the size and frequency of the tight junction for paracellular transport may be greater in dogs than in humans, which might explain the greater extent of absorption of small hydrophilic compounds, such as polyethylene glycol oligomers.44

5.03.6.2 Interspecies Differences in Distribution

The PK parameter that is most commonly used to characterize the distribution of a drug is its volume of distribution at steady state (VD ss). VD,ss represents the equivalent volume into which a given dose of drug is apparently distributed

Figure 8 Oral absorption in dog versus human of 43 drugs with markedly different physicochemical properties. (Reproduced from Chiou, W. L.; Jeong, H. Y.; Chung, S. M.; Wu, T. C. Pharm. Res. 2000, 17, 135-140.36)

Figure 8 Oral absorption in dog versus human of 43 drugs with markedly different physicochemical properties. (Reproduced from Chiou, W. L.; Jeong, H. Y.; Chung, S. M.; Wu, T. C. Pharm. Res. 2000, 17, 135-140.36)

within the body and, as such, it includes the extent to which the drug is bound to tissue and/or plasma proteins. The numerical value of VDss that is recorded can be as small as the blood volume or, for compounds that are extensively bound to tissues, can exceed the volume of total body water. The following equation has been proposed to relate VD ss to plasma and tissue binding:

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