Solubility systemic clearance

Knauf MJ, Bell DP, Hirtzer P, Luo ZP, Young JD, Katre NV (1988) Relationship of effective molecular size to systemic clearance in rats of recombinant interleukin-2 chemically modified with water-soluble polymers. J Biol Chem 263 15064—15070... 

In this project, compound A from a potential lead series was a neutral compound of MW 314 with low aqueous solubility (Systemic clearance, volume and AUC following a 0.5mg/kg intravenous dose to rats were well predicted (within twofold) from scaled microsomal clearance and in silica prediction of pKa, logP and unbound fraction in plasma. Figure 10.3a shows the predicted oral profile compared to the observed data from two rats dosed orally at 2mg/kg. The additional inputs for the oral prediction were the Caco-2 permeability and measured human fed-state simulated intestinal fluid (FeSSIF, 92(tg/mL). The oral pharmacokinetic parameters Tmax. Cmax. AUC and bioavailability were well predicted. Simulation of higher doses of compound A predicted absorption-limited... 

Bioavailability is influenced by many properties, depending on the rate and the extent of absorption and systemic clearance. Each of these properties is impacted by physicochemical properties such as solubility, log P, log D, and pKa. Absorption and metabolism are often governed by opposing factors. More lipophilic compounds tend to be more permeable, but solubility may also become a limiting factor. In addition, more lipophilic compounds will be more rapidly and extensively metabolized and will show increased toxicity liabilities [86]. 

Factors known to influence the clearance of drugs from interstitial sites, following extravasation or parenteral interstitial or transepithelial administration, include size and surface characteristics of particles, formulation medium, the composition and pH of the interstitial fluid, and disease within the interstitium. Studies indicate that soluble macromolecules smaller than 30 nm can enter the lymphatic system, whereas particulate materials larger than 50 nm are retained in the interstitial sites and serve as a sustained-release depot. The use of lipids or an oil in a formulation and the presence of a negative surface charge all appear to... 

Fig. 17. Biological model recommended for describing the uptake and retention of cerium by humans after inhalation or ingestion. Numbers in parentheses give the fractions of the material in the originating compartments which are cleared to the indicated sites of deposition. Clearance from the pulmonary region results from competition between mechanical clearances to the lymph nodes and gastrointestinal tract and absorption of soluble material into the systemic circulation. The fractions included in parentheses by the pulmonary compartment indicate the distribution of material subject to the two clearance rates however, these amounts will not be cleared in this manner if the material is previously absorbed into blood. Transfer rate constants or functions, S(t), are given in fractions per unit time. Dashed lines indicate clearance pathways which exist but occur at such slow rates as to be considered insignificant compared to radioactive decay of the cerium isotopes.

Clearance to pulmonary lymph nodes will occur at a fractional rate of 0.0001 per day. Dissolution of the deposited particles and absorption of cerium into the systemic circulation will occur at rates that are between the extremes represented by CeCh in CsCl particles and Ce oxide or Ce in fused aluminosilicate particles as given by the functions included in Figure 9. These rates should not be expected to be constant over the entire clearance period and will depend upon the overall composition of the bulk aerosol particles, which indude particle size, amount of stable lanthanide present, acidity, and the solubility of other components of the particles. The accuracy of predicting respiratory tract clearance and internal organ uptake of radiocerium will depend heavily upon adequate determination of the particle solubility characteristics. 

Substances, which can be inhaled, are sparingly soluble in water and fat, and of low systemic toxicity may cause adverse effects in the lung (irreversible impairment of lung clearance, lung fibrosis, and lung tumor formation), which can be explained by overload phenomena (EC 2003). 

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