Magnetic resonance imaging of macroscopic intrahepatic portal-hepatic venous shunts

Direct communication between portal branches and the hepatic vein [macroscopic intrahepatic portal-hepatic venous shunt (IPHVS)] is a rare entity. We have recently studied five patients with this condition. Magnetic resonance imaging (MRI) clearly demonstrated in each case the portal-hepatic venous shunt due to flow void. Multiple diffuse shunts were present in one case and a solitary shunt was demonstrated in the others. The solitary shunt was either tubular, focally dilated or racemose in configuration. The MRI findings and clinical significance of this rare entity are discussed.     

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.     

Clinical assessment of monoclonal antibodies for the treatment and diagnosis of colorectal cancers

The clinically useful monoclonal antibodies(Mabs) for colorectal cancers were reviewed. Since 1980's, immunoscintigraphy has been performed for the detection of occult colorectal cancers. However, it may be substituted with the development of positron emission tomography. As for the treatment, some Mabs have been shown to be effective for the adjuvant therapy of postoperative colorectal cancers. Some Mabs to epidermal growth factor receptors(EGFr) are quite promising since they block the functions necessary for the tumor growth and enhance the cytotoxicity of chemotherapy. Recent advances for the development of humanized Mabs will improve the chance of Mabs to be used as an effective adjuvant.     

Plasma 5'-nucleotidase activities increase in women with hyperemesis gravidarum

OBJECTIVES: To investigate plasma activities of 5'-nucleotidase, a key enzyme in the production of adenosine and evaluate the relationship between changes in 5'-nucleotidase activities and pregnancy-related hormones, estrogen, progesterone and human chorionic gonadotropin (hCG) in women with hyperemesis gravidarum. DESIGN AND METHODS: Plasma 5'-nucleotidase activities and estradiol, progesterone and hCG levels were measured in 21 women with hyperemesis gravidarum and normal pregnancies, matched for age, parity and gestational week. RESULTS: In women with hyperemesis gravidarum, plasma 5'-nucleotidase activities averaged 8.1 +/- 0.6 IU/L, which were significantly increased compared to those in normal pregnant women (5.5 +/- 0.5 IU/L)(p < 0.05). The increases in plasma 5'-nucleotidase activities were accompanied by elevations of plasma estradiol, progesterone and hCG levels. CONCLUSIONS: The increase of plasma 5'-nucleotidase activities may be at least partly attributed to elevations of pregnancy-related hormones, suggesting changes in purine metabolism in women with hyperemesis gravidarum.     

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.