Biomedical subjects
PJ Sinko
Publications and source records attributed to PJ Sinko.
Involvement of multiple transporters in the oral absorption of nucleoside analogues.
Many nucleoside analogues such as azt, ddI, ddC, d4T, 3TC, acv and vacv are currently being used in the treatment of patients infected with HIV, suffering from AIDS, or AIDS-related opportunistic infections. The transport of nucleoside analogues across the gastrointestinal tract is mediated by a number of transporters that fall into three broad categories, i.e., Na(+)-dependent concentrative transporters, Na(+)-independent equilibrative transporters and H(+)/peptide transporters. The first two transporter classes contain a large number of subtypes that are based on the substrate specificity. Recent studies have shown that most of the anti-HIV nucleoside analogues are transported by one or more of the nucleoside transporters. Furthermore, certain analogues, such as acv, appear to be absorbed by non-carrier-mediated diffusion, whereas vacv is apparently transported by non-nucleoside transporters (e.g., the oligopeptide transporter, PepT1 and possibly others). Thus, it is desirable to understand the precise nature of the absorption mechanism of these drugs to improve bioavailability and reduce the variability that is commonly observed in vivo in human patients. A complete understanding of the complex interactions of nucleoside analogues with the various transporters will help in designing better delivery systems and strategies to improve efficacy. In the current report, the mechanisms of nucleoside and nucleoside-analogue transport are reviewed. Also, methods of exploiting prodrugs to improve the bioavailability characteristics of drugs are highlighted.
Oral absorption of the HIV protease inhibitors: a current update.
Although the human immunodeficiency virus (HIV) protease inhibitors are highly effective, they are characterized by low and/or variable bioavailability with limited penetration into the central nervous system (CNS). Their clinical use is limited by patient compliance and by drug-drug interactions. The effect of drug solubility on their oral absorption has been investigated but further evaluation of this relationship is required. First pass metabolism appears to be significant for the HIV protease inhibitors and they are extensively metabolized by cytochrome P450 (CYP) 3A4. Recent studies suggest that these drugs are substrates for the P-glycoprotein efflux pump, which can limit their intestinal absorption and their transport across the blood-brain barrier. Drugs inducing or inhibiting CYP3A4 and/or P-glycoprotein may influence the bioavailability of the HIV protease inhibitors. The low bioavailability, variable absorption and drug-drug interactions of the HIV protease inhibitors may be related to the variability of cytochrome P450 and P-glycoprotein expression and to possible CYP3A4/P-glycoprotein interactions. To improve oral HIV protease inhibitor therapy, it is essential to mechanistically characterize the cell specific, tissue specific and regional intestinal dependencies of drug transport, secretory transport, metabolism and P-glycoprotein/CPY3A4 interactions. This report reviews the physicochemical characteristics and pharmacokinetics of the HIV protease inhibitors while considering the relationships between their hepatic and intestinal metabolism, low bioavailability, variable absorption and drug-drug interactions.
The effect of physical barriers and properties on the oral absorption of particulates.
This paper provides an in-depth review of the biological, immunological, and physicochemical barriers to the oral absorption of microparticles. The roles of the mucus and mucosal cell layers are discussed along with technologies and strategies that may be used to improve uptake, including attempts to determine the mechanisms of microparticulate uptake into enterocytes and membranous epithelial (M) cells. Considerations unique to the absorption of microparticles, such as particle size, surface characteristics, cell surface interactions, and the driving force for absorption of microparticles, are also addressed. Although the extent of absorption of microparticles is severely limited, this review provides insight into potential methods and technologies that have been and could be used to improve the oral absorption of microparticles.