Lipophilic drug absorption solubility

As most drugs are preferably given orally, absorption which is complete, consistent and predictable is desirable. Although it may be possible from solubility, lipophilicity, pKa, molecular size, and animal data to make some prediction about likely absorption, only a study in humans will give quantitative data as the mechanisms of drug absorption are complex and still incompletely understood (Washington et al., 2001). It may be helpful here to distinguish between the terms absorption and bioavailability. ... 

Generally, the stratum corneum is considered to be the rate limiting layer of the skin with regard to transdermal drug absorption. However, for the invasion of very lipophilic compounds, the bottleneck moves from the stratum corneum down to the viable, very hydrophilic layer of the epidermis, due to substances reduced solubility in this rather aqueous layer [14],... 

Although there appears to be no significant species differences in absorption rates for small lipophilic drugs, some interspecies differences are noted with water-soluble drugs absorbed from distal airspaces of in vivo mammalian lungs [112], These species differences have not been systematically studied yet. However, some marked differences were reported for protein absorption rates... 

Apart from being a diffusional barrier, mucin can also interact with drugs to decrease their bioavailability, as has been shown with tetracycline [106], phenylbutazone, and warfarin [107]. On the other hand, studies in rats showed that binding of some water-soluble drugs to intestinal mucus was essential for their absorption and that damage to the mucus significantly reduced absorption [108], The acidic mucus is essential for lipid absorption and could be important for the diffusion of lipophilic drugs (see below). 

The physicochemical properties of the drug molecules and the formulation can also influence rectal drug absorption (Table 7.1). Crucial parameters in this regard include drug concentration, molecular weight, solubility, lipophilicity, pKa, surface properties, and particle size [12]. In addition, formulation properties such as the nature of the suppository base material may play a critical role in regulating drug absorption. 

In summary, nasal epithelial intercellular junctions are less restrictive compared to the gastrointestinal tract. Such polar pathways will mainly be responsible for the transport of water-soluble compounds, providing a relatively slow, but significant route which is dependent on the molecular weight of the diffusing species. Secondly, transcellular (lipoidal) pathways permit extremely rapid absorption of lipophilic drugs with a rate dependency based on cell membrane partitioning. 

Another type of absorption enhancer, which has been shown to have a better safety profile, is cyclodextrin (CD) [39]. CDs have been shown to form inclusion complexes with lipophilic drugs, thereby improving their aqueous solubility and stability. A powdered insulin formulation containing dimethyl-(3-cyclodextrin improved the absolute bioavailability of insulin by 13% in rabbits compared to a control liquid formulation (1%) of insulin with dimethyl-(3-cyclodextrin [40]. Recently, hydroxypropyl (3-cyclodextrin has been shown to be more effective for enhancing the nasal absorption of acyclovir than a range of other absorption enhancers in vivo [41]. 

In 1985 a major step in the theoretical analysis of oral drug absorption phenomena took place [156], when solubility and dose were also taken into account for the estimation of the absorption potential A P of a drug apart from the pH-partition hypothesis related parameters (lipophilicity, and degree of ionization). According to this concept, the AP is related proportionally to the octanol/water partition coefficient Pc, the fraction of the un-ionized species, at pH= 6.5, and the physiological solubility cs of the drug and inversely proportional to the dose r/o ... 

Pale stools indicate partial or complete (if the stools are white) blockage of the bile ducts, such that reduced or no bile is excreted. This will affect the absorption of highly lipophilic drugs, e.g. fat-soluble vitamins, as no bile salts will be secreted into the duodenum to solubilise fats. It will also mean that drugs that are cleared exclusively by the bdiary system will have significantly reduced clearance. 

Permeability and solubility/dissolution are two major determinants of gastrointestinal drug absorption. The prediction of solubility of molecules is more difficult than for lipophilicity. Solubility critically depends on the solid-state properties of compounds. The same compound can exist in amorphous or in several crystalline states and this can result in very different solubility of molecules. The prediction of crystalline properties, represented, for example, by the melting point, is one of the most difficult problems of physical chemistry. Like the octanol-water partition coefficient, water solubility critically depends on the pH and ionization state of molecules. 

On the other hand, highly lipophilic compounds, such as hormones, can be solubilized via the prodrug approach. For example, the rate of transdermal absorption of the highly lipophilic drug, testosterone, was enhanced over 50-fold by forming water-soluble, yet lipophilic, prodrug ester.f The prodrug testoster-onyl-4-dimethylaminobutyrate was found to penetrate human skin tissue, in vitro, 54 times faster than... 

---