Drug partition coefficients

Tab. 4.30 Drug partition coefficients into biological membranes and octanol-buffer. (Reprinted from Tab. 2 of ref. 95 with permission from the American Chemical Society)...

The rate at which distribution takes place into a tissue is dependent on both the drug partition coefficient (concentration in tissue/concentration in blood at equilibrium) and the blood flow to that tissue. The higher the perfusion rate (blood flow per unit volume of tissue), the more rapid is equilibrium achieved between blood and tissue. The higher the partitioning into the tissue, the longer reaching equilibrium takes, as more drug has to be transported to the tissue. 

Figure 9.25 (a) Drug partition coefficient and solubility dependence on vehicle composition for the ideal case, (b) Predicted relative steady-state penetration (QP) as a function of vehicle composition for the ideal case. Point A represents a formulation containing 1.0 mg g and 60% solubiliser. On threefold dilution with a base containing no solubiliser, point B is arrived at where C,P is higher. 

The HYBOT descriptors were successfully applied to the prediction of the partition coefficient log P (>i--octanol/water) for small organic componnds with one acceptor group from their calculated polarizabilities and the free energy acceptor factor C, as well as properties like solubility log S, the permeability of drugs (Caco-2, human skin), and for the modeling of biological activities. 

The partition coefficient and aqueous solubility are properties important for the study of the adsorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) of drugs. The prediction of the ADME-Tox properties of drug candidates has recently attracted much interest because these properties account for the failure of about 60 % of all drug candidates in the clinical phases. The prediction of these properties in an early phase of the drug development process could therefore lead to significant savings in research and development costs. 

Concerning the distribution of a drug, models have been published for log BB blood/brain partition coefficient) for CNS-active drugs (CNS, central nervous system) crossing the blood-brain barrier (BBB) [38-45] and binding to human serum albumin (HSA) [46]. 

Essex J W, C A Reynolds and W G Richards 1989. Relative Partition Coefficients from Partition Functions A Theoretical Approach to Drug Transport. Journal of the Chemical Society Chemical Communications 1152-1154. 

General anaesthetics have been in use for the last 100 years, yet their mechanism of action are still not yet clearly defined. For many years it was thought that general anaesthetics exerted their effects by dissolving in cell membranes and perturbing the lipid environment in a non-specific manner. This theory derived from the observation that for a number of drugs which induced anaesthesia, their potency correlated with their oil-water partition coefficients. This Meyer-Oveiton correlation was accepted for a number of years, however in the last 15-20 years evidence has shown that a more likely theory is that of specific interactions of anaesthetics with proteins, particularly those within the CNS that mediate neurotransmission [1]. 

The ending caine stems from cocaine, the first clinically employed local anaesthetic. Procaine and tetracaine are ester-linked substances, the others are amides. Amide bonded local anaesthetics usually contain two i s in their name, ester-bonded only one. In the structure drawings, the lipophilic portion of the molecule is depicted at the left, the amine at the right. The asterisk marks the chiral centre of the stereoisomeric drugs. Lipid solubility is given as the logarithm of the water octanol partition coefficient, log(P). 

The toxicological or cumulative effect of illicit drugs on the ecosystems has not been studied yet. Moreover, their fate and transport in the environment is to a big extent still unknown. Due to their physical-chemical properties (octanol-water partition coefficient, solubility, etc.) some of them, such as cannabinoids, are likely to bioaccumulate in organisms or concentrate in sediments whereas the rest, much more polar compounds, will tend to stay in aqueous environmental matrices. However, continuous exposure of aquatic organisms to low aquatic concentrations of these substances, some of them still biologically active (e.g., cocaine (CO), morphine (MOR) and MDMA) may cause undesirable effects on the biota. 

It is poorly soluble in acetone, 2-butanone, ethyl acetate, acetonitrile, and DMF, and insoluble in alcohols, petroleum ether, and diethyl ether. The partition coefficients of a number of solutes between PCL and water have been measured and correlated with octanol-water partition coefficients (Fig. 9) (58,59). The linear correlation (Eq. 2) when combined with the water solubility of the solutes serves as a method of estimating the solubility of drugs in PCL from first principles. ... 

An analysis of partition coefficient data and drug solubilities in PCL and silicone rubber has been used to show how the relative permeabilities in PCL vary with the lipophilicity of the drug (58,59). The permeabilities of copolymers of e-caprolactone and dl-lactic acid have also been measured and found to be relatively invariant for compositions up to 50% lactic acid (67). The permeability then decreases rapidly to that of the homopolymer of dl-lactic acid, which is 10 times smaller than the value of PCL. These results have been discussed in terms of the polymer morphologies. 

From an analysis of the key properties of compounds in the World Dmg Index the now well accepted Rule-of-5 has been derived [25, 26]. It was concluded that compounds are most Hkely to have poor absorption when MW>500, calculated octanol-water partition coefficient Clog P>5, number of H-bond donors >5 and number of H-bond acceptors >10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The Rule-of-5 should be seen as a qualitative absorption/permeabiHty predictor [43], rather than a quantitative predictor [140]. The Rule-of-5 is not predictive for bioavail-abihty as sometimes mistakenly is assumed. An important factor for bioavailabihty in addition to absorption is liver first-pass effect (metaboHsm). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [141, 142]. 

Polar surface area (PSA) - defined simply as the part of a molecular surface that is polar - is probably, together with the octanol-water partition coefficient, one of the most important parameters used to characterize the transport properties of drugs. PSA has been shown to provide very good correlations with intestinal... 

Nys, G. G., Rekker, R. F. Statistical analysis of a series of partition coefficients with special reference to the predictability of folding of drug molecules. Introduction of hydrophobic fragmental constants (/-values). Chim. Therap. 1973, 8, 521-535. 

A general definition of log P and log D, in its simplest form, can be given as the logarithm of the ratio (P or D) of the concentration of species of interest (the drug in a pharmaceutical context) in each phase, assuming the phases are immiscible and well separated prior to analysis. P is defined as the partition coefficient, whereas D is the distribution coefficient. However, the simplest form does not reveal some of the intricacies of the determination and use of these parameters, and further explanation is necessary. 

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