Tissue, binding

Methyl paraoxon may also be made unavailable by binding to noncritical tissue and plasma constituents (Benke and Murphy 1975), including cholinesterase (Parkinson 1996). In addition, the parent compound is bound to albumin, in serum, as discussed previously in Section 3.4.2.4, but this binding does not appear to limit the availability of methyl parathion to the tissues, indicating that it is reversible. Tissue binding appears to be more important than serum binding (Braeckman et al. 1980, 1983). 

Binding affinity inhibition constant X (tiM) versus [ HJoxytocin in rat uterine tissue. Binding affinity inhibition constant Kj (tiM) versus [ HJarginine vasopressin in rat liver tissue. Binding affinity inhibition constant AT (tiM) versus [ H] arginine vasopressin in rat kidney tissue. 

Above 5 Low solubility and poor oral bioavailability. Erratic absorption. High metabolic liability, although potency may still be high. Basic amines tend to show high to very high Vd (Volume of distribution = ratio of overall tissue binding to plasma protein binding)... 

The volume of distribution of many drugs is significantly increased or decreased in patients with CKD. Changes result from altered protein or tissue binding, or pathophysiologic alterations in body composition (e.g., fractional contribution of total body water to total body weight). 

Let s consider now the food chain. Chemicals that accumulate in one organism at one trophic level in the food chain (a prey) due to tissue binding are further... 

Some physiological volumes are known or have been estimated. Over two decades ago, Oie and Tozer proposed a relationship between the volume of distribution of a drug and its extent of plasma and tissue binding, using various fixed values for plasma and extracellular fluid volumes [1], This equation has been utilized in some methods used for prediction of steady-state VD, which will be discussed later ... 

Over the years, various tissues and tissue components have been discussed as compartments into which drugs can penetrate and bind. The ability of lipophilic drugs to partition into membranes has been known for many years, especially cationic drugs that can bind to anionic phospholipid membranes [15-20]. The phenomenon of lysosomal trapping has also been cited as a factor that contributes to the tissue binding and high VD values of weakly basic drugs [20-23]. 

For purposes of this discussion, in vitro methods for predicting VD are divided into two categories (1) tissue binding approaches and (2) correlation to experimentally determined physio-chemical properties. 

The conclusion was offered that binding into blood cells represents a reasonable surrogate of tissue binding, as blood cells would contain similar compositions to major tissue depots for drug binding. 

The overall accuracy of the predictions, assessed as the mean-fold error of prediction of the test set was 2.03, making this approach one that would possess suitable accuracy for use in drug design and human pharmacokinetic predictions. Similar methods developed separately for acids and bases showed an improvement in accuracy. This investigation also included a prediction of unbound VD, which should represent a simpler parameter to predict since it would be based only on tissue binding and not plasma protein binding. However, it is interesting to note that this approach was less accurate for this parameter, which would be unexpected. 

Allometry (unbound VD) Determinants of tissue binding scale with body weight across species VDSS in two or more animal species, /u in animals and human 16]... 

Dog-human proportionality Dog and human tissue binding capacities are similar VDSS in dog, fu in dog and human 16]... 

Rabbit muscle homogenate binding Muscle tissue binding dominates all tissue binding and muscle binding in rabbit and human is similar Fraction unbound in muscle homogenate by dialysis [25]... 

Blood cell partitioning Red blood cell binding is representative of tissue binding Human blood cell/buffer partition ratio [26]... 

Correlation to elogD and fraction ionized Tissue binding of bases and neutrals is primarily driven by lipophilicity and cationic character elogD, pKa, /u in human [32]... 

In vitro methods Tissue binding assays. If no in vivo models are available, in vitro methods combined with in vivo testing in a pharmacologically nonreactive may suffice. 

Presence of competitive binding substances (e.g., specific receptor sites in tissues bind drugs). 

Calu-3 cells have shown the ability to perform fatty acid esterification of budes-onide [132], In pre-clinical studies, this esterification results in a prolonged local tissue binding and efficacy, which is not found when the esterification is inhibited [133]. The precise mechanism remains undefined in that the identity of specific enzyme(s) responsible for this metabolic reaction is unclear [134], Assessment of the potential toxicity and metabolism of pharmaceuticals and other xenobiotics using in vitro respiratory models is still at its infancy. The development of robust in vitro human models (i.e., cell lines from human pulmonary origin) has the potential to contribute significantly to better understanding the role of biotransformation enzymes in the bioactivation/detoxication processes in the lung. 

Brandt I, Brittebo EB, Kowalski B, et al. 1987. Tissue binding of 1,2-dibromoethane in the cynomolgus monkey (Macaca fascicularis). Carcinogenesis 8 1359-1361. 

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