Abstract

A serious pharmacokinetic interaction between cerivastatin (CER) and gemfibrozil (GEM) has been reported. In the present study, we examined the inhibitory effects of GEM and its metabolites, M3 and gemfibrozil 1-O-␤-glucuronide (GEM-1-Oglu), on the uptake of CER by human organic anion transporting polypeptide 2 (OATP2)-expressing cells and its metabolism in cytochrome P450 expression systems. Uptake studies showed that GEM and GEM-1-O-glu significantly inhibited the OATP2-mediated uptake of CER with IC 50 values of 72 and 24 M, respectively. They also inhibited the CYP2C8-mediated metabolism of CER with IC 50 values of 28 and 4 M, respectively, whereas M3 had no effects. GEM and GEM-1-O-glu minimally inhibited the CYP3A4-mediated metabolism of CER. The IC 50 values of GEM and GEM-1-O-glu for the uptake and the metabolism of CER obtained in the present study were lower than their total, and not unbound, plasma concentrations. However, considering the possibly concentrated high unbound concentrations of GEM-1-O-glu in the liver and its relatively larger plasma unbound fraction compared with GEM itself, the glucuronide inhibition of the CYP2C8-mediated metabolism of CER appears to be the main mechanism for the clinically relevant drug-drug interaction. Previously reported clinical drug interaction studies showing that coadministration of GEM with pravastatin or pitavastatin, both of which are known to be cleared from the plasma by the uptake transporters in the liver, only minimally (less than 2-fold) increased the area under the plasma concentration-time curve of these statins, also supported our present conclusion.

Recent studies have revealed the import role played by transporters in the renal and hepatobiliary excretion of many drugs. These transporters exhibit a broad substrate specificity with a degree of overlap, suggesting the possibility of transporter-mediated drug-drug interactions with other substrates. This review is an overview of the roles of transporters and the possibility of transporter-mediated drug-drug interactions. Among the large number of transporters, we compare the Ki values of inhibitors for organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs) and their therapeutic unbound concentrations. Among them, cephalosporins and probenecid have the potential to produce clinically relevant OAT-mediated drug-drug interactions, whereas cyclosporin A and rifampicin may trigger OATP-mediated ones. These drugs have been reported to cause drug-drug interactions in vivo with OATs or OATP substrates, suggesting the possibility of transporter-mediated drug-drug interactions. To avoid adverse consequences of such transporter-mediated drug-drug interactions, we need to be more aware of the role played by drug transporters as well as those caused by drug metabolizing enzymes.

The mechanism involved in the clinically relevant drug-drug interaction (DDI) between cerivastatin (CER) and cyclosporin A (CsA) has not yet been clarified. In the present study, we examined the possible roles of transporter-mediated hepatic uptake in this DDI.

Treatment with 6 mg/d capsinoids orally appeared to be safe and was associated with abdominal fat loss. Capsinoid ingestion was associated with an increase in fat oxidation that was nearly significant. We identified 2 common genetic variants that may be predictors of therapeutic response.

High power and high efficiency nonpolar m-plane (1100) nitride light emitting diodes (LEDs) have been fabricated on low extended defect bulk m-plane GaN substrates. The LEDs were grown by metal organic chemical vapor deposition (MOCVD) using conditions similar to that of c-plane device growth. The output power and external quantum efficiency (EQE) of the packaged 300 ×300 µm2 was 23.7 mW and 38.9%, respectively, at 20 mA. The peak wavelength was 407 nm and <1 nm redshift was observed with change in drive current from 1–20 mA. The EQE shows a minimal drop off at higher currents.

The aim of this study was to develop an objective evaluation system for the masticatory function. This system used paraffin wax cubes as a test food, which had six red- and green-coloured layers so that each of the six surfaces showed a pseudo-checkered pattern. A total of 100 paraffin cubes were chewed by 37 subjects and the images of these samples were captured and analysed using a digital image analyzer. With regard to the colour and the shape of each sample, five parameters were obtained. Furthermore, an independent examiner graded the degree of colour mixing in the chewed samples into three groups (poor, medium and good) by visual inspection. A discriminant analysis was performed using the five variables as predictors of two groups (good and poor). Mixing Ability Index (MAI) was calculated from the discriminant function and using this index, 97% of the samples from these two groups were classified correctly. This system needed only a few minutes to complete and is easy to use. Therefore, it has high potentials for clinical use.

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