Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil

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-beta-glucuronide (GEM-1-O-glu), 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 microM, respectively. They also inhibited the CYP2C8-mediated metabolism of CER with IC(50) values of 28 and 4 microM, 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.     

Contribution of organic anion transporters to the renal uptake of anionic compounds and nucleoside derivatives in rat

Our previous kinetic analyses have shown that rat organic anion transporter 1 (rOat1; Slc22a6) and rOat3 (Slc22a8) are responsible for the renal uptake of p-aminohippurate and pravastatin, respectively. In this study, their contribution to the renal uptake of organic anions and nucleoside derivatives was examined by investigating the uptake by rOat1- and rOat3-expressing cells and kidney slices. Transfection of rOat1 resulted in an increase of the uptake of temocaprilat (Km = 0.56 microM), 2,4-dichlorophenoxyacetate (2,4-D; Km = 10 microM), and 3'-azido-3'-deoxythymidine (AZT; Km = 43 microM). rOat3-expressing cells showed significant uptake of temocaprilat (Km = 1.4 microM), estrone sulfate (Km = 5.3 microM), dehydroepiandrosterone sulfate (DHEAS; Km = 12 microM), and benzylpenicillin (PCG; Km = 85 microM). All the test compounds were accumulated in kidney slices in a carrier-mediated manner, although the saturable components of AZT and acyclovir were small. The Km of 2,4-D uptake by kidney slices was comparable with that of rOat1, and the corresponding values of DHEAS and PCG were similar to those of rOat3. The uptake of estrone sulfate and temocaprilat by kidney slices consisted of two saturable components, with the Km values of their high-affinity components being similar to those for rOat3 (estrone sulfate), and rOat1 and rOat3 (temocaprilat), respectively. These results suggest that the renal uptake of 2,4-D is mainly accounted for by rOat1 and the uptake of PCG and DHEAS by rOat3, and rOat3 is partly involved in the renal uptake of temocaprilat and estrone sulfate.     

Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin

Pravastatin is a well known 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. Cumulative studies have shown that pravastatin is taken up into hepatocytes by the organic anion transporting polypeptide family transporters and excreted into the bile as an intact form by multidrug resistance-associated protein 2 (MRP2). It is generally accepted that the bile salt export pump (BSEP/ABCB11) mainly transports bile acids and plays an indispensable role in their biliary excretion. Interestingly, we found that BSEP could accept pravastatin as a substrate. Significant ATP-dependent uptake of pravastatin by human BSEP (hBSEP)- and rat BSEP (rBsep)-expressing membrane vesicles was observed, and the ratio of the uptake activity of pravastatin to that of taurocholic acid (TCA) by hBSEP was 3.3-fold higher than that by rBsep. The K(m) value of pravastatin for hBSEP was 124 muM. A mutual inhibition study between TCA and pravastatin revealed that they competitively interact with hBSEP. Several statins inhibited the hBSEP- and rBsep-mediated uptake of TCA; however, the specific uptake of other statins (cerivastatin, fluvastatin, and pitavastatin) by hBSEP and rBSEP was not detected. The inhibitory effects of hydrophilic statins (pravastatin and rosuvastatin) on the uptake of TCA by BSEP were relatively lower than those of lipophilic statins. These data suggest that BSEP may be partly involved in the biliary excretion of pravastatin in both rats and humans.     

Application of boron-entrapped stealth liposomes to inhibition of growth of tumour cells in the in vivo boron neutron-capture therapy model.

Tumour cell destruction in boron neutron-capture therapy (BNCT) is due to the nuclear reaction between (10)B and thermal neutrons. It is necessary for effective BNCT therapy to accumulate (10)B atoms in the tumour cells. The delivery system consisted of polyethylene-glycol (PEG) binding liposomes (DPPC/cholesterol/DSPC-PEG2000) with an entrapped (10)B-compound and we evaluated the cytotoxic effects of intravenously injected (10)B-PEG-liposomes on human pancreatic carcinoma xenografts in nude mice with thermal neutron irradiation. After thermal neutron irradiation of mice injected with (10)B-PEG-liposomes, growth of AsPC-1 tumours was suppressed relative to controls. Injection of (10)B-PEG-liposomes caused the greatest tumour suppression with thermal neutron irradiation in vivo. These results suggest that intravenous injection of (10)B-PEG-liposomes can increase the retention of (10)B atoms by tumour cells, causing suppression of tumour growth in vivo, after thermal neutron irradiation.     

The utilization of fluorescent cholangiography during robotic cholecystectomy at an inner-city academic medical center

In recent years, fluorescent cholangiography using Indocyanine green (ICG) dye has been used to aid identification of structures during robotic cholecystectomy. We sought to compare cholecystectomy with ICG dye versus laparoscopic cholecystectomy at an inner-city academic medical center. Between January 2013 and July 2016, we identified 287 patients of which 191 patients underwent laparoscopic cholecystectomy and 96 patients underwent robotic cholecystectomy with ICG dye. Preoperative risk variables of interest included age, sex, race, body mass index (BMI), and acute cholecystitis. Primary outcome of interest was conversion to open procedures while secondary outcome was length of stay. The two groups were similar in their BMI (31.98 vs. 31.10 kg/m² for the laparoscopic and robotic, respectively, p = 0.32). The laparoscopic group had a greater mean age compared to the robotic group (47.77 vs. 43.61 years, p = 0.04). There was no significant difference in sex and emergency surgery between the two groups. Fewer open conversions were found in the robotic than the laparoscopic group [2 (2.1%) vs. 17 (8.9%), p = 0.03]. In multiple logistic regression, robotic cholecystectomy with ICG also showed a lower risk of conversion compared to laparoscopic cholecystectomy, but the difference did not reach statistical significance (OR 0.42, 95% CI 0.11–1.65, p = 0.22). ICG fluorescent cholangiography during robotic cholecystectomy may contribute to proper identification of biliary structures and may reduce the rates of open conversion. The preliminary results of fewer open conversions are promising. Further studies with a large randomized prospective controlled study should be taken for further evaluation.     

Surgical Outcomes of Pancreaticoduodenectomy for Pancreatic Cancer with Proximal Dorsal Jejunal Vein Involvement

Background/Purpose

The proximal jejunal vein which branches from the dorsal side of the superior mesenteric vein (SMV) usually drains the inferior pancreatoduodenal veins (IPDVs) and contacts the uncinate process of the pancreas. We focused on this vein, termed the proximal dorsal jejunal vein (PDJV), and evaluated the anatomical classification of the PDJV and surgical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) with PDJV involvement (PDJVI).

Methods

The jejunal veins that branch from the dorsal side of the SMV above the inferior border of the duodenum are defined as PDJVs. We investigated 121 patients who underwent upfront pancreaticoduodenectomy for PDAC between 2011 and 2017; PDJVs were resected in all patients. The anatomical classification of PDJV was evaluated using multidetector computed tomography. Surgical and prognostic outcomes of pancreticoduodenectomy for PDAC with PDJVI were evaluated.

Results

The PDJVs were classified into seven types depending on the position of the first and second jejunal veins relative to the superior mesenteric artery. In all patients, the morbidity and mortality rates were 15.7 and 0.8%, respectively. The rates for parameters including SMV resection, presence of pathological T3–4, R0 resection, and 3-year survival were 46.2, 92.3, 92.3, and 61.1%, respectively, when there was PDJVI (n?=?13). When there was no PDJVI (n?=?108), the rates were 60.2, 93.5, 86.1, and 58.3%, respectively. Overall, there were no significant differences.

Conclusions

Pancreaticoduodenectomy with PDJV resection is feasible for PDAC with PDJVI and satisfactory overall survival rates are achievable. It may be necessary to reconsider the resectability of PDAC with PDJVI.

     

Clinical assessment of Er,Cr:YSGG laser application for cavity preparation

In this study, an erbium,chromium:YSGG (Er,Cr:YSGG) laser emitting at a wavelength of 2.78 microm was clinically applied to remove caries and prepare cavities, and the clinical outcome was evaluated. Effective clinical application of Er,Cr:YSGG laser had been expected from previous studies. This study included 44 patients (26 females, 18 males; aged 23-58) with a total of 50 cavity preparations by the Er,Cr:YSGG laser irradiation at 3-6 W with water spray. Patient acceptance and prognosis were evaluated. Most cases (94%) were prepared without anesthesia, and no pain was felt in 34 cases (68%). No adverse reaction was observed in any of the cases, and patient acceptance for this system was favorable. All cases had a good prognosis. In 45 cases (90%), overall clinical evaluation was satisfactory. From the present study, it can be concluded that the Er,Cr:YSGG laser system is an efficient, effective, and safe device for caries removal and cavity preparation.     

Mechanisms of Long-Latency Paired Pulse Suppression: MEG Study

Brain Topography - Paired pulse suppression is an electrophysiological method used to evaluate sensory suppression and often applied to patients with psychiatric disorders. However, it remains...