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Methods and Principles in Medicinal Chemistry - Mannhold R.

Mannhold R., Kubinyi H., Timmerman H. Methods and Principles in Medicinal Chemistry - Wiley-VCH, 2001. - 155 p.
Download (direct link): pharmacokinetiksmedicanalchemistri2001.pdf
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The actual amount of a drug absorbed (Fa) is dependent on two rates: the rate of absorption (ka) and the rate of disappearance of the drug from the absorption site. Disappearance can be due to absorption (ka) or movement of the drug (km) through the gastrointestinal tract and away from the absorption site. The proportion absorbed can be expressed as:
Fa= ka/(ka + km) (3.3)
Compounds crossing the gastrointestinal tract via the transcellular route can usually be absorbed throughout the length of the tract. In contrast the paracellular route is only, readily, available in the small intestine and the term “absorption window” is often applied. The calculated human pore sizes (radii) are, jejunum 6-8 A, ileum 2.9-3.8 A and colon less than 2.3 A. In practice the small intestine transit time is around 6 h whilst transit of the whole tract is approximately 24 h. For lipophilic compounds, with adequate dissolution, which have high rates of transcellular passage across membranes, ka has a high value. Moreover, since the drug is absorbed throughout the g.i. tract km is of a low value and therefor the proportion of a dose absorbed is high (complete). For hydrophilic compounds, which are dependent on the slow paracellular pathway, ka has a low value. Moreover, the “absorption window” referred to above means that the drug rapidly moves away from the absorption site and km is high. Consequently paracellularly absorbed compounds show incomplete absorption and the proportion which is absorbed is low. Table 3.1 gives examples of compounds absorbed by the paracellular route.
What is noticeable is that the compounds are of low molecular weight, however, there is no simple relationship between molecular weight and percentage absorbed, probably indicating that shape and possibly flexibility are also of importance. Compounds such as propranolol (log D74, 0.9) which are related to those in Table 3.1,
3.3 Membrane Transfer | 39 Tab. 3.1 Examples of drugs absorbed by the paracellular route.
Compound log D7.4 Molecular weight % Absorbed
Nadolol -2.1 309 13
Sotalol -1.7 272 100
Atenolol -1.5 266 51
Practolol -1.3 266 100
Xamoterol -1.0 339 9
Amosulalol -0.8 380 100
Sumatriptan -0.8 295 60
Pirenzipine -0.6 351 25
Famotidine -0.6 338 37
Ranitidine - 0.3 314 50

show high flux rates via the transcellular route and consequently are completely absorbed. Note, however, that lipophilicity correlates with increased metabolic lability and such compounds may have their apparent systemic availabilities decreased by metabolism as they pass through the gut and the liver.
For simple molecules, like р-adrenoceptor antagonists octanol/water log D74 values are remarkably predictive of absorption potential. Compounds with log D74 values below 0 are absorbed predominantly by the paracellular route and compounds with log D74 values above 0 are absorbed by the transcellular route.
Another example of the relationship between log D values and intestinal absorption is taken from reference [1] (see Figure 3.4). Compounds with log D >0 demonstrate a nearly complete absorption. Two exceptions are compounds with a MW above 500. Whether size as such, or the accompanying increase in the number of H-bonds, is responsible for poorer absorption is not fully understood.
Fig. 3.4 Dependence of oral absorption on log D [1].
However, as the number of H-bonding functions in a molecule rises, octanol/ water distribution, in isolation, becomes a progressively less valuable predictor. For such compounds desolvation and breaking of H-bonds becomes the rate-limiting step in transfer across the membrane [7].
40 3 Absorption
Octanoi/Cyclohexane Ratio (H-bonding)
Ten Amine (2.5) sec Amine (4.5) Pri Amine (5.1)
Alkyl Ester (2.4) Amide (8.6)
Phenyl Ether (1.8) Carboxylate (4.7)
Halogen (<1) Ketone (1.8) Hydroxyl (3.2)
Nitrile (1.7) Sulphonamide (10.0)
Nitro (0.8) Sulphone (4.1)
Sulphoxide (3.1)
Fig. 3.5 Raevsky H-bond scores from HYBOT95 (shown in parentheses) and correlation with Dlog D (compare with Figure 1.2 in Chapter 1).
Methods to calculate H-bonding potential range from simple H-bond counts (number of donors and acceptors), through systems that assign a value of 1 for donors and 0.5 for acceptors to sophisticated scoring systems such as the Raevsky H-bond score [8]. The correlation of Raevsky H-bond scores with Alog D shown previously as Figure 1.4 in Chapter 1 (Physicochemistry) is shown as Figure 3.5.
None of these methods gives a perfect prediction, particularly because H-bonding potential needs to be overlaid over intrinsic lipophilicity. For this reason Lipinski’s “rule-of-five” becomes valuable in defining the outer limits in which chemists can work [9]. Lipinski defined the boundaries of good absorption potential by demonstrating that poor permeability is produced by:
• more than five H-bond donors (sum of OHs and NHs)
• more than 10 H-bond acceptors (sum of Ns and Os)
• molecular weight over 500
• poor dissolution by log P over 5
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