Drug distribution tissue partition coefficient

Drugs with low partition coefficients are likely to distribute in the plasma and thus are more likely to have peripheral effects. They are also more likely to be eliminated by renal fdtration. In contrast, those with high partition coefficients will distribute in adipose tissue and are more likely to cross the blood-brain barrier and distribute into the central nervous system (CNS), with CNS effects. These drugs are likely to undergo hepatic metabolism and be eliminated in the bile. 

Olive oil was the original model lipid for partition studies, and was used by Overton in his pioneering research [518,524], It fell out of favor since the 1960s, over concerns about standardizing olive oil from different sources. At that time, octanol replaced olive oil as the standard for partition coefficient measurements. However, from time to time, literature articles on the use of olive oil appear. For example, Poulin et al. [264] were able to demonstrate that partition coefficients based on olive oil-water better predict the in vivo adipose-tissue distribution of drugs, compared to those from octanol-water. The correlation between in vivo log Kp (adipose tissue-plasma) and log (olive oil-water) was 0.98 (r2), compared to 0.11 (r2) in the case of octanol. Adipose tissue is white fat, composed mostly of triglycerides. The improved predictive performance of olive oil may be due to its triglyceride content. 

Bjorkman, S. (2002) Prediction of the volume of distribution of a drug which tissue-plasma partition coefficients are needed Journal of Pharmacy and Pharmacology, 54, 1237-1245. 

Considering the different composition of phospholipids in membranes, it would be expected that the distribution of drugs into tissues and their localization therein would differ, and that the partition coefficients in membranes, log PM, would deviate in size and ranking from those determined in bulk octanol-water. Log PM can be strongly affected by the presence of charged head groups in the phospholipids, especially in the case of amphiphihc dmgs. 

Detailed in vivo studies on the tissue distribution in rabbits of a set of 10 drugs have been reported together with their partition coefficients, Kp, in various tissues and partition coefficients log Papp in four solvent systems octanol, benzene, chloroform, and triolein [91]. The results are summarized in Table 4.26. The Kp values in the studied tissues, including bones, showed a large variation in ranking and a significant variation from tissue to tissue. It was found that the tissue-to-plasma partition coefficient of the non-ionized form of the dmgs, Kf,(w correlates best with log Poet. of the non-ionized form. 

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. 

Prior to 2002, most studies published on physiologically-based pharmacokinetic models focused on the distribution and elimination of environmental toxins such as dioxin, styrene, and organic solvents [68-70]. PBPK models for drug molecules generally relied on tissue/plasma partition coefficients (Kps) measured in rat [71-73]. 

Volume of distribution at steady state (Fdss) can also be predicted with in vitro measured compound affinity to different tissues. This affinity is quantitated by tissue to plasma partition coefficients (Kp or Kpu) obtained by in vitro incubation of different tissue homogenates with compound of interest [25,26], Coupled with the known physiological information in preclinical and clinical species, such as lipid, protein, and water content in each tissue, this mechanistic approach should provide good prediction in humans. However, this approach is very labor intensive therefore it is not typically used in most drug discovery applications. 

The low concentration of protein in the interstitial fluid has been suggested as another factor which may reduce the distribution of some substances in the central nervous system. Lipid soluble compounds, such as methyl mercury which is toxic to the central nervous system (see Chapter 7). can enter the brain readily, the facility being reflected by the partition coefficient. Another example which illustrates the importance of the lipophilicity in the tissue distribution and duration of action of a foreign compound is afforded by a comparison of the drugs thiopental and pentobarbital (figure 3,5). These drugs are very similar in structure, only differing by one atom. Their pKa values are similar and consequently the... 

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