Lipid solubility oral bioavailability

As examples of the range of oral bioavailability a very lipid-soluble drug such as the anticonvulsant phenytoin, or the steroidal anti-inflammatory compound prednisolone, would normally have an oral bioavailability greater than 90%, whereas a very lipid-insoluble drug such as the antibiotic, neomycin, has an oral bioavailability of less than 1%. 

Drug A is a large, peptide-like molecule (MW 700 g/mol) and is highly lipophilic and poorly water soluble. It is a BCS Class II drugs. Its oral bioavailability in capsules and conventional tablet formulations is low, yielding practically undetected blood levels. A novel lipid formulation containing a solvent, a high HLB nonionic surfactant, and a fatty acid were developed with sufLcient oral bioavailability for use in the clinic. 

In this chapter we will provide a brief overview of the early approaches to bioavailability enhancement by use of simple lipid-based delivery systems (lipid solutions, emulsions etc), and then describe recent progress in the application of self-emulsifying- and microemulsion-based formulations. The effects of lipids on the oral bioavailability of co-administered poorly water-soluble drugs may also be classified from a mechanistic (and to a degree, historical) perspective as physicochemically mediated effects (solubility, dissolution, surface area) and biochemically mediated effects (metabolism, transport related events), and these will be approached separately. It is readily apparent, however, that in many cases physicochemically and biochemically mediated mechanisms will operate side by side. In some instances, bioavailability may also be enhanced by the stimulation of intestinal lymphatic transport, and these studies will be addressed in a separate section. 

In addition to their usefulness in the enhancement of oral bioavailability of lipophilic drugs, microemulsion formulations have found considerable application as potential delivery systems for peptides whose delivery is often limited by poor GI permeability. W/O microemulsions provide a convenient means of delivery of both permeability-enhancing lipids and water-soluble peptides. The GI permeability-enhancing effects of lipids and their use in the delivery of highly water-soluble compounds are reviewed elsewhere [18, 56, 59],... 

Further studies have validated this hypothesis, in part,4 and ultimately this inventive premise was borne out in clinical practice. As a result, 5-FU (5) was eventually approved for treatment of solid tumors, such as breast, colorectal, and gastric cancers. Marketed as Adrucil when administered intravenously, 5-FU can be used either as monotherapy or combination therapy with various cytotoxic drugs and biochemical modulators, such as leucovorin and methotrexate.5 Because 5-fluorouracil is not orally bioavailable, it must be administered by continuous infusion to optimize its efficacy due to its short half-life in plasma. In addition, 5-FU has poor selectivity toward tumors in vivo, and its distribution into tissues such as bone marrow, the gastrointestinal tract, the liver and skin causes high incidences of toxicity. In addition, in spite of its limited lipid solubility, 5-fluorouracil diffuses readily across the blood-brain barrier into cerebrospinal fluid and brain tissue.1,5... 

Prochlorperazine fulfils the criteria for efficient transmucosal delivery it is a highly lipid soluble base with a pKa of 8.1 and is therefore largely non-ionized at salivary pH. Because first-pass metabolism is avoided, the bioavailability via the buccal route is much higher than via the oral route (Figure 7.2). 

Absorption and distribution The TCAs are well absorbed upon oral administration, and because of their lipophilic nature, are widely distributed and readily penetrate into the CNS. This lipid solubility also causes these drugs to have long half-lives, for example, 4 to 17 hours for imipramine. As a result of their variable first pass metabolism in the liver, TCAs have low and inconsistent bioavailability. Therefore the patient s response is... 

Lipid-based formulations of poorly water soluble drugs offer large versatility for oral administration as they can be formulated as solutions, gels, suspensions, emulsions, self-emulsifying systems, multiple emulsions, microemulsions, liposomes, and solid dispersions. " Administration of a drug in a lipidic vehicle/formu-lation can enhance the absorption and oral bioavailability via a combination of various mechanisms " " that are briefly summarized as follows ... 

Phenobarbital is absorbed rapidly and well after oral administration to horses, with bioavailability approaching 100% (Ravis et al 1987). It is distributed widely into the tissues but, because of its lower lipid solubility, does not distribute into the CNS as rapidly as other barbiturates. After i.v. administration, it may take 15-20 min before therapeutic concentrations of phenobarbital are reached in the CNS. Phenobarbital primarily undergoes hepatic metabolism and only 25% is excreted as unchanged drug. The half-lives reported in horses, around 18-24 h (Duran et al 1987, Knox et al 1982, Ravis et al 1987) and 12 h in foals (Spear et al 1984), are substantially shorter than in other species, meaning that steady-state concentrations can be achieved more rapidly. 

Propranolol is a lipid-soluble drug that undergoes rapid hepatic metabolism, resulting in a short half-life (2h). Rapid first-pass metabolism results in a low bioavailability and therapeutic plasma concentrations are rarely achieved in the horse after oral administration (Muir Mcguirk 1987). The drug can only administered i.v. and plasma concentrations are increased if hepatic blood flow is reduced, e.g. by significant cardiac disease. 

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