Distribution tissue partition coefficient

Other important determinants of the effects of compounds, especially solvents, are their partition coefficients, e.g., blood-tissue partition coefficients, which determine the distribution of the compound in the body. The air-blood partition coefficient is also important for the absorption of a compound because it determines how quickly the compound can be absorbed from the airspace of the lungs into the circulation. An example of a compound that has a high air-blood partition coefficient is trichloroethane (low blood solubility) whereas most organic solvents (e.g., benzene analogues) have low air-blood partition coefficients (high blood solubility). 

In a first stage, distribution was predicted with tissue composition-based equations and the estimated tissue partition coefficients were combined with clearance estimated by direct scaling of hepatocyte intrinsic clearance in a PBPK model as described earlier. 

The inhalational anesthetics have distinctly different solubility (affinity) characteristics in blood as well as in other tissues. These solubility differences are usually expressed as coefficients and indicate the number of volumes of a particular agent distributed in one phase, as compared with another, when the partial pressure is at equilibrium (Table 25.3). For example, isoflurane has a blood-to-gas partition coefficient (often referred to as the Ostwald solubility coefficient) of approximately 1.4. Thus, when the partial pressure has reached equilibrium, blood will contain 1.4 times as much isoflurane as an equal volume of alveolar air. The volume of the various anesthetics required to saturate blood is similar to that needed to saturate other body tissues (Table 25.3) that is, the blood-tissue partition coefficient is usually not more than 4 (that of adipose tissue is higher). 

There are two types of parameters that can be employed to represent the extent of distribution in PK models. The first is a tissue partition coefficient Kj), and the second is a volume of distribution (F). The definition of each of these parameters is provided in the following sections. 

Dmg distribution into tissue reservoirs depends on the physicochemical properties of the dmg. Tissue reservoirs include fat, bone, and the principal body organs. Access of dmgs to these reservoirs depends on partition coefficient, charge or degree of ionization at physiological pH, and extent of protein binding. Thus, lipophilic molecules accumulate in fat reservoirs and this accumulation can alter considerably both the duration and the concentration—response curves of dmg action. Some dmgs may accumulate selectively in defined tissues, for example, the tetracycline antibiotics in bone (see Antibiotics,tetracyclines). 

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. 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

Partition coefficients (nonpolar chemicals are distributed more readily to fat tissues than are polar chemicals). 

The specific mechanisms by which mirex and chlordecone are transferred from the gut, lungs, or skin to the blood are not known. However, mirex is a highly stable, lipophilic compound that is resistant to metabolism. It has a high lipid water partition coefficient, so it partitions readily into fat and demonstrates a very high potential for accumulation in tissues. The preferential distribution of chlordecone to the liver rather than to the fat tissue is due to its association with plasma proteins. 

The partition coefficients of these compounds ranged from 25 (bis-methyl diatrizoate) to 10 ° (derivative of 2 with a C18 chain length of the carboxylic acid). Tissue distribution studies in mice showed good liver uptake of these substances, particularly for those with intermediate chain lengths. No human data have been reported so far. 

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. 

There are several physiochemical properties of the toxicant that can influence its distribution. These include lipid solubility, pKa, and molecular weight, all of which were described earlier in this chapter (Section 6.4) and will not be described here. For many toxicants, distribution from the blood to tissues is by simple diffusion down a concentration gradient, and the absorption principles described earlier also apply here. The concentration gradient will be influenced by the partition coefficient or rather the ratio of toxicant concentrations in blood and tissue. Tissue mass and blood flow will also have a significant effect on distribution. For example, a large muscle mass can result in increased distribution to muscle, while limited blood flow to fat or bone tissue can limit distribution. The ratio of blood flow to tissue mass is also a useful indicator of how well the tissue is perfused. The well perfused tissues include liver,... 

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