Current Drug Metabolism - Volume 11, Issue 9, 2010

Oral bioavailability is a function of intestinal absorption and first-pass metabolism. Future chemistry space is predicted to be relatively hydrophilic; where the development issues associated with toxicity are expected to be low [1]. This may result in limited passive membrane permeability and increased reliance on membrane transporters for intestinal absorption. A growing list of membrane transporters has been recognized in Read More

Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism. Although there are various enzymes in the gut wall which may contribute to gut first pass metabolism, Cytochrome P450 (CYP) 3A has been shown to play a major r Read More

While oral exposure continues to be the major focus, the chemical space of recent drug discovery is apparently trending towards more hydrophilic libraries, due to toxicity and drug-interactions issues usually reported with lipophilic drugs. This trend may bring in challenges in optimizing the membrane permeability and thus the oral absorption of new chemical entities. It is now apparent that the influx transporters such as pe Read More

Experimental strategies have long been applied for in vitro or in vivo evaluation of the effect of transporters and/or enzymes on the bioavailability. However, the lack of specific inhibitors or inducers of transporters and enzymes and the multiplicity of nuclear receptors in gene regulation and cross-talk have led to compromised assessments of these effects in vivo. These and other causes have resulted in confusion and contro Read More

Recently, interest has grown in drug-drug interactions (DDIs) involving the inhibition of intestinal CYP3A4, P-glycoprotein (P-gp), and other drug efflux transporters. The criteria for intestinal DDIs are described in the draft guidances of the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Substrate drugs with small fraction absorbed (Fa) and/or low intestinal availability (Fg) as a result of intestinal e Read More

Successful delivery of promising new chemical entities via the oral route is rife with challenges, some of which cannot be explained or foreseen during drug development. Further complicating an already multifaceted problem is the obvious, yet often overlooked, effect of dietary substances on drug disposition and response. Some dietary substances, particularly fruit juices, have been shown to inhibit biochemical processes in Read More

The bioavailability of therapeutic agents can be improved by using prodrugs which have better passive diffusion than the active agents. Intestinal hydrolysis is an important reaction in the bioconversion of prodrugs, and may be the rate-limiting factor in their absorption. Carboxylesterase (CES) is ubiquitous in most organs and is located in the endoplasmic reticulum. Single-pass perfusion experiments in rat intestine have shown t Read More

The screening of new drug candidates for nuclear receptor activation can identify agents with the potential to produce drugdrug interactions or elicit adverse drug effects. The nuclear receptors of interest are those that control the expression of drug metabolizing enzymes and drug transporters, and include the constitutive androstane receptor (CAR, NR1I3), the pregnane X receptor (PXR, NR1I2) and the aryl hydroca Read More

A review with 132 references. Several kinds of anxiolytic and hypnotic drugs are currently available on the market. Although BZDs are surely the most frequently prescribed among them, several chemically unrelated compounds have been commercialised, which can provide similar or even higher efficacy and tolerability. These drugs can prove useful for patients who are non-responder or intolerant to benzodiazepine treatm Read More