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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.
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26 Van de Waterbeemd H, In: Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical and Computational Strategies (Eds Testa B, Van de Waterbeemd H, Folkers G, Guy R), Verlag HCA, Basel, 2001, pp. 499-511.
Pharmacokinetics and Metabolism in Drug Design 47 Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman I
Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)
CNS Central nervous system Symbols
Clp Plasma clearance
Clu Unbound clearance of free drug
Alog P Difference in log P values in octanol and cyclohexane
H-bond Hydrogen bond
kel Elimination rate constant
log D7.4 Distribution coefficient at pH 7.4 (usually octanol/water)
log P Partition coefficient (usually octanol)
pK Ionization constant
Tmax Time to maximum observed plasma concentration
Vd(f| Unbound volume of distribution of the free drug
Membrane Transfer Access to the Target
Distribution of drugs across the membranes of the body can be regarded as passive diffusion. Similar considerations to those already outlined for oral absorption apply, although for significant penetration to intracellular targets the aqueous pore pathway does not readily apply. Similarly, as previously outlined the tight junctions of the capillaries supplying the CNS render the paracellular pathway very inefficient. These aspects of distribution were also described in Section 2.10, concerning the unbound drug model and barriers to equilibrium. Figure 4.1 depicts a scheme for the distribution of drugs. Penetration from the circulation into the interstitial fluid is rapid for all drugs since the aqueous pores present in capillary membranes have a mean diameter of between 50-100 A. Thus there is ready access to targets located at the surface of cells such as G-protein coupled receptors. The exception to this is the cerebral capillary network, since here there is a virtual absence of pores due to the continuous tight intercellular junctions. For intracellular targets, if only the free drug is
48 4 Distribution
Fig. 4.1 Schematic illustrating drug distribution. Drug is pres-Plasma ent 'n the circulation as either free or bound, only the free drug is available for distribution, bound drug 1 in tissues is the drug bound to intracellular proteins and constituents, Tissue bound drug 2 is that bound to the cell and intracellular membranes.
considered, then at steady state the concentrations present inside the cell and in the circulation should be similar for a drug that readily crosses the cell membrane.
The overall amount of drug present in a tissue is determined by the amount that is bound either to intracellular proteins or, as discussed below, to the actual cell membranes themselves. Albumin is present in many tissues and organs and is available to bind drugs. Other intracellular proteins that can bind drugs include ligandin, present in liver, kidney and intestine, myosin and actin in muscular tissue and melanin in pigmented tissue, particularly the eye. Normally, as previously discussed, the free drug is that which determines the pharmacological activity. Note also, as previously stated, that the concentration of free drug in the circulation depends at steady state on free drug clearance and not the extent of plasma protein or even blood binding. In certain instances, as will be highlighted later, certain toxicities can derive directly due to membrane interactions (disruption, phospholipidosis, etc.). Key factors which determine the ease of crossing cell membranes are, lipophilicity, as defined by partition coefficient, hydrogen bonding capacity [1] and molecular size [2]. For simple small molecules with a minimum of nitrogen- or oxygen-containing functions, a positive log D value is a good indicator of ability to cross the membrane. For more complex molecules, size and H-bonding capacity become important.
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