Lipid solubility pharmacokinetics

Another type of therapeutically active molecule is one designed primarily with pharmacokinetics in mind (designed to be well absorbed and to enter the central compartment readily), which can then be converted to the therapeutically active molecule in the body. These are referred to as pro-drugs. This process, called latentiation, consists of the conversion of hydrophilic drugs into lipid-soluble drugs (usually by masking hydroxyl, carboxyl, and... 

Figure 5,4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details...

In the present compilation of the distribution and pharmacokinetic data of a dozen xenobiotics studied in the dogfish shark, this species yielded excellent data consistent with what we know from similar studies on terrestrial mammals. The data from the shark occasionaly provided information not available in other animals. Major transport parameters in this fish were shown to be similar to those found in mammals. This aquatic organism handles lipid-soluble pollutants by sequestering them in its fatty liver. Together with a previous summary (23) we have now studied about three dozen xenobiotics in this species. Because of its ease of handling, low cost, abundance, predictive value of transport mechanisms, and well-developed pharmacokinetics, the dogfish shark is an ideal fish species to use as a model to study aquatic pollutants. 

If both maternal and embryo-fetal toxicity have ensued, a frequent interpretation is that the maternal toxicity has caused the embryo-fetal toxicity. In the author s view, it is more likely that a dose that is toxic to the adult is going to be toxic to the conceptus, and there is no need to invoke undefined (and probably indefinable) indirect mechanisms. Particularly in the case of small molecules that are lipid-soluble and that can cross the placenta freely, the maternal and fetal systems could be said to constitute a single pharmacokinetic compartment, and the conceptus will be exposed directly to the drug. It would not be surprising if the conceptus manifested effects of toxicity in cases where adult toxicity has been shown. 

Pharmacokinetics Well absorbed after PO administration. Protein binding 97%. Undergoes first-pass metabolism. Is highly lipid soluble. Primarily excreted in feces. Half-life 4 hr. 

Ibtal body accumulation reflects both total intake and the rate of elimination. Factors important in the rate of elimination include pharmacokinetics, lipid solubility, metabolism of the parent compound, profile of metabolites formed, rate of formation of reactive intermediates, degree of enzyme induction, amount of relevant covalent binding with subceUular macromolecules, and the rate of removal from the cell... 

Water-soluble avoids the use of solubilising agents No pain on injection, no venous or tissue damage following extravasation Pharmacokinetics High lipid solubility, a high proportion of unbound, unionised drug to facilitate... 

Reasons for variability in the dose required for pharmacological and adverse effects are partly pharmacokinetic. Thus, due to the lipid solubility, there is a big volume of distribution. Accumulation can occur because of the long half-life, and renal dysfunction is an important cause of variability in digitoxin toxicity. Thus, as renal function is an important factor in the half-life and blood level, half-lives of up to six days can occur in patients with compromised function (compared with 36-48 hours in normal patients). 

Pharmacokinetic properties Intravenous alfentanil (Hull, 1983) has a rapid onset and a short duration of action. It has a shorter elimination time (terminal half-life 1-2 h) than fentanyl. It is less lipid-soluble and the short duration of action is more dependent on metabolic inactivation than on redistribution. Alfentanil has a high (90%) plasma protein binding. Metabolic inactivation is effected by oxidative N- and O-demethylation. 

The permeability, P (P = Pc x D), of a nonpolar substance through a cell membrane is dependent on two physicochemical factors (1) solubility in the membrane (Pc), which can be expressed as a partition coefficient of the drug between the aqueous phase and membrane phase, and (2) diffusivity or diffusion coefficient (D), which is a measure of mobility of the drug molecules within the lipid. The latter may vary only slightly among toxicants, but the former is more important. Lipid solubility is therefore one of the most important determinants of the pharmacokinetic characteristics of a chemical, and it is important to determine whether a toxicants is readily ionized or not influenced by pH of the environment. If the toxicant is readily ionized, then one needs to understand its chemicals behavior in various environmental matrices in order to adequately assess its transport mechanism across membranes. 

In the sections below, four different cases for converting biomonitoring data to exposure dose using pharmacokinetic modeling are considered lipid-soluble, bioaccumulative chemicals at steady state lipid-soluble, bioaccumulative chemicals not at steady state shorter-half-life chemicals at... 

Case Example of Use of One-Compartment Pharmacokinetic Model to Estimate Intake Dose of Slowly Cleared Lipid-Soluble Chemicals 2,3,7,8-TCDD... 

GC-MS methods provide greater specificity and in many cases sensitivity when compared with more conventional techniques. They offer increased scope for the study of pharmacokinetics and of plasma concentration in relation to biological effect. SIM assay has been applied to the investigation of placental transfer of lipid soluble drugs and their subsequent elimination in the newborn (barbiturates, diphenylhydantoin, caffeine, pethidine and diazepam [122,408] diphenylhydantoin [411] amylobarbitone and 3 -hydroxyamylobarbitone [83,423]). 

Pharmacokinetic lipid-soluble, water-soluble, see above. 

Deficiencies. The current model for the cause of vitamin E deficiencies points to malabsorption of lipids. Thus, there may be malabsorption of other lipid-soluble vitamins. Little is known regarding the pharmacokinetics of the tocopherols. Part of the reason for this may be attributed to lack of a specific storage organ for the vitamin. 

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