1alpha,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), a natural ligand of the vitamin D receptor (VDR), was found to increase the rat ileal Asbt and bile acid absorption. The effects of VDR, whose expression is low in liver, on hepatic transporters and enzymes are unknown. Protein and mRNA levels of target genes in the small intestine, colon and liver after intraperitoneal dosing of 1,25(OH)(2)D(3) (0-2.56 nmol/kg/day for 4 days) to the rat were determined by Western blotting and qPCR, respectively. The 1,25(OH)(2)D(3) treatment increased total Cyp3a protein and Cyp3a1 mRNA expressions in the proximal small intestine, and the short heterodimer partner (SHP), the fibroblast growth factor 15 (FGF15), organic solute transporter (Ostalpha and Ostbeta) mRNA and Asbt protein expressions in the ileum. About 50% higher portal bile acid concentration (65.1+/-14.9 vs 41.9+/-7.8 microm, p<0.05) and elevated expressions of the hepatic farnesoid X receptor (FXR) and SHP mRNA resulted with 1,25(OH)(2)D(3) treatment. Increased Bsep and Ostalpha mRNA expressions in liver and a>50% reduction in the Cyp7a1 protein level (p<0.05) and cholesterol metabolism in rat liver microsomes (p=0.002), likely consequences of the bile acid-FXR-SHP cascade and activation of the signaling pathway for Cyp7a1 inhibition by FGF15, were found. Increased hepatic multidrug resistance-associated protein (Mrp3) and multidrug resistance protein 1a (Mdr1a) mRNA and P-gp protein were also observed. It was concluded that the changes in hepatic transporters and enzymes in the rat were indirect, secondary effects of the liver FXR-SHP cascade due to increased intestinal absorption of bile acids and elevated levels of FGF15, events that led to the activation of FXR.

This review highlights the "interplay" between enzymes and transporters, essential components of eliminating organs for drug removal. The understanding of the interplay is important in terms of deciphering the change of one eliminatory pathway on compensatory mechanisms in drug disposal, and, ultimately, their importance in drug-drug interactions. Controversy existed on the explanation underlying the interplay between transporters and enzymes in the Caco-2 cell monolayer or cell culture systems, but less so on eliminating organs such as the intestine and liver. For the Caco-2 system, the increase in the mean residence time (MRT) accompanying increased secretion had been construed as the basis for increased metabolism. We hold the opposite view and assert that increased secretion should evoke a decrease in metabolism due to the competition between the enzyme and apical efflux transporter for the drug within the cell. To illustrate this point, simulations on the MRT, fraction of dose metabolized (f(met)) and the extraction ratio (ER) as defined by various investigators under linear and nonlinear metabolic conditions were compared to observed data and the trends upon induction/inhibition of secretion. The conclusion is that the f(met) is the more appropriate index to reflect the extent of metabolism in transporter-enzyme interplay, since the parameter captures drug metabolism in the cell when its contents in the apical, cell, and basolateral compartments or the entire dose is considered to be available for metabolism. This parameter for metabolism (f(met)) bears a reciprocal relationship to the secretory intrinsic clearance and is in concordance with the notion that both the enzyme and apical transporter compete for the cellular substrate within. For the liver and intestine, several physiologically based pharmacokinetic (PBPK) models that contain transporters and enzymes were utilized, together with the solved equations for the area under the curve (AUC), metabolic, excretory, and total clearance (CL) to shed meaningful insight of how the inhibition of one pathway can result in a higher AUC and therefore a reduced total clearance for drug, but a higher apparent clearance of the alternate pathway; induction of the same pathway would lead to an increased total clearance but decreased drug AUC, and reduced clearance of the alternate pathway. The use of an increased MRT to explain increased extents of metabolism upon increased apical excretion is not tenable in these organs or "open systems" since the MRT of drug in the cell is reduced with irreversible loss from biliary excretion or hastened gastrointestinal transit of the secreted drug in the lumen. Data in the literature for the Caco-2 system, knockout animals and organ perfusion systems were discussed in relation to these concepts on clearance based on fundamental, pharmacokinetic theory. The shortcomings in data interpretation were discussed. The general conclusion is that a reciprocal relationship exists between the clearances related to enzymes and apical transpo...

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have emerged as potential drug delivery systems for various applications that are produced from physiological, biodegradable, and biocompatible lipids. The methods used to produce SLNs and NLCs have been well investigated and reviewed, but solvent injection method provides an alternative means of preparing these drug carriers. The advantages of solvent injection method include a fast production process, easiness of handling, and applicability in many laboratories without requirement of complicated instruments. The effects of formulations and process parameters of this method on the characteristics of the produced SLNs and NLCs have been investigated in several studies. This review describes the methods currently used to prepare SLNs and NLCs with focus on solvent injection method. We summarize recent development in SLNs and NLCs production using this technique. In addition, the effects of solvent injection process parameters on SLNs and NLCs characteristics are discussed.

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ABSTRACT:The objective of this study was to investigate the transport kinetics of cyclosporin A, a well known substrate for P-glycoprotein (P-gp), across the blood-brain barrier (BBB), and the expression of the transporter in the brain of streptozotocin-induced diabetic rats. The in vivo transport clearance of cyclosporin A was significantly reduced in diabetic rats compared with that in the control.

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P-glycoprotein (P-gp) is crucial in the active transport of various substrates with diverse structures out of cells, resulting in poor intestinal permeation and limited bioavailability following oral administration. P-gp inhibitors, including small molecule drugs, natural constituents, and pharmaceutically inert excipients, have been exploited to overcome P-gp efflux and enhance the oral absorption and bioavailability of many P-gp substrates. The co-administration of small molecule P-gp inhibitors with P-gp substrates can result in drug–drug interactions and increased side effects due to the pharmacological activity of these molecules. On the other hand, pharmaceutically inert excipients, including polymers, surfactants, and lipid-based excipients, are safe, pharmaceutically acceptable, and are not absorbed from the gut. Notably, they can be incorporated in pharmaceutical formulations to enhance drug solubility, absorption, and bioavailability due to the formulation itself and the P-gp inhibitory effects of the excipients. Different formulations with inherent P-gp inhibitory activity have been developed. These include micelles, emulsions, liposomes, solid lipid nanoparticles, polymeric nanoparticles, microspheres, dendrimers, and solid dispersions. They can bypass P-gp by different mechanisms related to their properties. In this review, we briefly introduce P-gp and P-gp inhibitors, and we extensively summarize the current development of oral drug delivery systems that can bypass and inhibit P-gp to improve the oral absorption and bioavailability of P-gp substrates. Since many drugs are limited by P-gp-mediated efflux, this review is helpful for designing suitable formulations of P-gp substrates to enhance their oral absorption and bioavailability.