Lipophilicity and metabolism

The DDT group insecticides are environmentally persistent because they have very low water solubility and vapor pressure and moderate stability to sunlight. For example, the water solubility of DDT is less than 2 ppb (parts per billion), and its vapor pressure is 1.5 x 10 7 mm Hg at 20°C. These compounds are also highly lipophilic and metabolically stable. As a result, they are persistent biologically and tend to bioaccumulate. The toxicity of this group is low... 

The fate of chlordane in the body reflects the lipophilicity and metabolism of the chemical. 

The pk of tetrazole in DMSO (8.2) is higher than acetic acid (12.3), although both have a similar aqueous pK values [157]. Eurthermore, tetrazoles due to their higher solubility, lipophilicity and metabolic stability than analogous carboxylic acids are... 

In the present series, indolyl-triazole 93 has the best overall profile in terms of D3R affinity, selectivity, lipophilicity, and metabolic stability. 

Lewis, D. F., Lake, B. G., Ito, Y., Anzenbacher, P. Quantitative structure-activity relationships (QSARs) within cytochromes P450 2B (CYP2B) subfamily enzymes the importance of lipophilicity for binding and metabolism. Drug Metab. Drug Interact. 

The thyroid hormones are lipophilic and relatively insoluble in the plasma. Therefore, they are transported throughout the circulation bound to plasma proteins such as thyroxine-binding globulin (75%) and albumins (25%). Approximately 99.96% of circulating thyroxine is protein bound. Bound hormone is not available to cause any physiological effects however, it is in equilibrium with the remaining 0.04% that is unbound. This free form of the hormone is able to bind to receptors on target tissues and cause its effects. Thyroid hormone has many metabolic effects in the body ... 

The development of synthetic methods for the selective introduction of short-chain perfluoroalkyl groups into organic molecules is of interest in drug development [464]. Fluoromodifications often confer unique properties on a molecule, for example in terms of increased metabolic stability and lipophilicity and, as a consequence, the pharmacokinetic profiles are often improved [465]. Burger and coworkers developed a domino process consisting of a SN reaction combined with a Claisen and a Cope rearrangement which allows the transformation of simple fluorinated compounds into more complex molecules with fluoro atoms [466]. Treatment of furan 2-917 with 2-hydroxymethyl thiophene (2-918) in the presence... 

Recently, Silva et al. have compared several techniques that have been applied to colonial marine invertebrates [13]. Catalan et al. [37] developed a technique in which sponges maintained in aquaria are attached to a plastic plaque. On the plaque, the sponge can be transferred, first to a smaller, aerated, vessel for treatment with an ethanolic or ethereal solution of the desired precursor. Then, after an incorporation period for uptake of the precursor, the sponge is returned to the sea, where metabolism is allowed to proceed in the animal s natural habitat. Silva et al. [13] found that optimal incubation time depended on the sponge, but generally was 20 to 90 days. These authors also reported on the effectiveness of lipophilic compared to hydrophilic precursors the former were taken up and metabolized more efficiently in sponges than hydrophilic ones. 

There are pharmacokinetic differences among /1-blockers in first-pass metabolism, serum half-lives, degree of lipophilicity, and route of elimination. Propranolol and metoprolol undergo extensive first-pass metabolism. Atenolol and nadolol have relatively long half-lives and are excreted renally the dosage may need to be reduced in patients with moderate to severe renal insufficiency. Even though the half-lives of the other /J-blockers are much shorter, once-daily administration still may be effective. /J-Blockers vary in their lipophilic properties and thus CNS penetration. 

Bioavailability can be assessed early in the discovery process by combining data from a number of independent in vitro assays run as part of a pharmaceutical properties profile. These assays generally include some measurement of aqueous solubility, lipophilicity, cell or membrane permeability, and metabolic stability. In most cases, proper interpretation of... 

The fate of a drag in vivo is dictated by a variety of physiochemical properties, including size, lipophilicity, and charge. These properties determine how a drag is absorbed into the blood, distributed throughout the body, metabolized, and eventually eliminated. While movement of a drug molecule can occur through simple diffusion, there are many transporter proteins expressed on cell membranes to assist... 

All these compounds are moderately lipophilic and should show excellent ability to cross biological membranes by transcellular absorption. Propranolol, betaxolol and metoprolol all have minimal gut first-pass metabolism, as shown by the low value for E(g. i.). Metabolism and first pass effects for these compounds are largely confirmed to the liver as shown by the values for E(g. i.). In contrast talinolol shows high extraction by the gastrointestinal tract with low liver extraction [13]. These effects are illustrated graphically in Figure 3.9 which shows the bioavailability predicted from hepatic extraction contrasted with that seen in vivo in man. 

Rather than looking at a metabolic pathway, similar models for the control of the mechanism of clearance by lipophilicity are demonstrated by considering drugs in general. Figure 5.7 illustrates free drug renal and metabolic clearance for a series of neutral compounds drawn from the literature [4]. 

Fig. 5.7 Relationship between lipophilicity and unbound renal (squares) and metabolic clearance (triangles) for a range of neutral drugs in...

While most lipophilic and large molecules are primarily excreted by the hepatobiliary system, the kidney is the major excretory organ for many small organic and inorganic molecules, drugs and hydrophilic metabolites, maintenance of fluid balance, and bone metabolism. These functions expose the kidney to a number of clinical, physiological, and pathological conditions that may compromise renal function. Some renal disorders that necessitate clinical intervention are listed in Table 2. 

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