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processes and the main factors limiting the oral bioavailability it is possible to perform dosing and/or sampling of the hepatic portal vein in animals in addition to the traditional methods of oral and intravenous dosing coupled with intravenous sampling. Thus, for example, fg and fh can be easily derived from these experiments and the respective contribution of gut and liver first pass effects can be easily quantified. Studies to investigate the relative contributions of the gut and liver to the first-pass loss of a number of compounds have been performed using in vivo intestinal-vascular access port models in various species including rat, dog, and rabbit. In order to assess and differentiate the roles of the intestine and liver with respect to metabolism and secretion, test compounds needed to be coadministered with specific P-gp and CYP3A inhibitors.

5.03.5.3 Studies to Assess Blood-Brain Barrier Permeation

Drugs that are effective against diseases in the central nervous system and reach the brain via the blood compartment must pass the blood-brain barrier (BBB). This is considered to be the most important barrier for drug transport to the brain because its surface area is 5000 times larger than the blood-cerebrospinal fluid barrier located at the choroid plexus.30 Compounds can cross the BBB by passive processes including paracellular transport for small hydrophilic compounds and transcellular transport for lipophilic compounds. Other possibilities include transcytosis with involvement of transporters. A number of transporters have been studied. Among these, the discovery of the presence of P-gp has greatly contributed to our understanding of the transport of compounds into the brain.30

Various methods are available to study the transport of compounds into the brain including in silico (see 5.31 In Silico Models to Predict Brain Uptake), in vitro (see 5.13 In Vitro Models for Examining and Predicting Brain Uptake of Drugs), and in vivo methods. The in vivo methods available to study brain transport include the single carotid injection technique, the internal carotid artery perfusion technique, the intravenous injection technique with brain tissue of cerebrospinal fluid (CSF) sampling, and in vivo brain microdialysis. These methods have been reviewed recently31 and are summarized in this section.

5.03.5.3.1 Carotid artery injection technique

With this technique the test compound is rapidly injected or perfused into the carotid artery32 This technique has been applied to various animal species including rats, mice, and guinea pigs. The brain is collected 5-15 s after administration of the compound to assess brain permeability. This technique has been widely used to study BBB permeability and the role of protein binding and transport in penetration to the brain.

5.03.5.3.2 Intravenous injection technique with brain collection

In this case, the compound is usually administered in the femoral vein through bolus injection or through infusion. Then, animals are sacrificed at different time points to allow brain and blood collection. The concentrations measured in brain and plasma are then used to assess brain permeability or determine the brain:plasma ratio at steady-state.

5.03.5.3.3 Cerebrospinal fluid sampling technique

The determination of CSF concentration has been attractive because of its low protein content and analysis of CSF samples is simple. Furthermore, there have been a number of examples indicating that CSF exposure might be related to exposure at the site of action. However, these observations cannot be generalized as a number of examples have also shown that the permeability at the blood-CSF barrier (the choroid plexus) could also be different from the BBB permeability.

For drugs that are passively transported, the CSF concentration may approximate unbound concentration in plasma. Jezequel33 compared the CSF to plasma concentration ratio with the free fraction in plasma for 50 drugs. About 50% of the compounds had a CSF to plasma concentration ratio similar to free fraction in plasma. For the other compounds, the unbound concentration in CSF was usually lower than the corresponding unbound concentration in plasma, most likely as a result of the involvement of active transport processes at the blood-CSF barrier.

5.03.5.3.4 Intracerebral microdialysis

These techniques have been reviewed recently.30 Intracerebral microdialysis involves the stereotactic implantation of a microdialysis probe in the brain. The probe comprises a semipermeable membrane partly covered with impermeable coating. The probe can be positioned at a specific site in the brain and may be used to sample extracellular fluid but also to deliver compound to the brain. One important issue of microdialysis experiments is the careful determination of in vivo concentration recovery for each experiment to characterize the relation between brain extracellular concentration and dialyzate concentration.

Intracerebral microdialysis is particularly suitable to estimate extracellular unbound drug concentration as a function of time. In addition unbound concentrations can be measured at the same time in blood and compared to unbound brain concentration to characterize drug transport across the BBB. The microdialysis technique offers the possibility to take multiple samples from individual animals and to sample from different brain regions including diseased brain sites for example.

A number of examples illustrate the applicability of microdialysis to study drug transport to the brain.34 Thus, the extracellular concentrations of atenolol and acetaminophen were shown to follow very closely the corresponding plasma concentrations. As a result of higher lipophilicity leading to larger lipophilic diffusion across the BBB, the extracellular fluid concentrations of acetaminophen were much larger than those of atenolol.34

5.03.6 Interspecies Differences in Pharmacokinetics

5.03.6.1 Species Differences in Absorption

Drug absorption is influenced by a variety of physiological and physicochemical factors. The physiological factors are species dependent and include gastric and intestinal transit time, blood flow rate, gastrointestinal pH and first-pass metabolism, while the physicochemical factors correspond to drug-specific and species-independent properties, such as pKa, molecular size, solubility, and lipophilicity. The oral bioavailability of a drug is defined as the fraction of an oral dose that reaches the systemic circulation unchanged. The oral bioavailability (F) can be described by eqn [1]. Thefa is determined mainly by solubility and stability of the drug in the gastrointestinal tract and its permeability across the intestinal membrane. Models for human bioavailability are given in Chapter 5.29.

In comparing oral bioavailability across animal species, it is not unusual to observe marked interspecies differences (Figure 5).

For many compounds, these differences reflect presystemic (intestinal and/or hepatic) drug metabolism. By contrast to presystemic metabolism and oral bioavailability, some similarities across species35-38 have been reported for fraction absorbed fa) as described below in more detail.

5.03.6.1.1 Physiology of the gastrointestinal tract

A recent review article has highlighted a number of similarities and differences in anatomy and physiology of the GI tract in rats and humans, which need to be taken into consideration in the interpretation of species differences in oral absorption39 For example, the human GI tract is capable of absorbing materials faster and to a greater extent than that of the rat. Such differences are likely to influence the extent to which drugs are absorbed. Overall, the rat's gastrointestinal tract is organized in the same way as the human's, but with a few important differences. For example, the relative lengths of the small intestine in the rat differ from those in man, in that the jejunum makes up nearly the entire small intestine in the rat. Another important difference is that the human intestinal tract is only about 5.5 times the length of that in the rat, despite man's much larger body size (70kg) compared to the rat (0.25 kg). The absolute surface area of the human intestinal tract is about 200 times that of the rat, which when normalized on the basis of body surface area amounts to a factor of 4 times. The physiological consequences of these anatomical differences are twofold.

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