Muneaki Hidaka

Effects of pomegranate juice on human cytochrome P450 2C9 and tolbutamide pharmacokinetics in rats

In this study, we investigated whether pomegranate juice could inhibit CYP2C9 activity. The ability of pomegranate juice to inhibit the diclofenac 4′-hydroxylase activity of human CYP2C9 was examined using human liver microsomes. Pomegranate juice was shown to be a potent inhibitor of human CYP2C9. The addition of 25 μl (5% v/v) of pomegranate juice resulted in almost complete inhibition of human CYP2C9 activity. In addition, we investigated the effect of pomegranate juice on the pharmacokinetics of tolbutamide (substrate for CYP2C9) in rats. Relative to the control group, the area under the concentration-time curve was approximately 1.2-fold greater when pomegranate juice (3 ml) was injected p.o. 1 h before the p.o. administration of the tolbutamide (20 mg/kg). The elimination half-life of tolbutamide was not altered by pomegranate juice administration. These results suggest pomegranate juice ingestion inhibits the intestinal metabolism of tolbutamide without inhibiting the hepatic metabolism in rats. Thus, we discovered that pomegranate juice inhibited human CYP2C9 activity and furthermore increased tolbutamide bioavailability in rats.

Effect of P-Glycoprotein Modulator, Cyclosporin A, on the Gastrointestinal Excretion of Irinotecan and Its Metabolite SN-38 in Rats

AbstractPurpose. The purpose of this work was to investigate the role of the hepatic and intestinal P-glycoprotein (P-gp) and canalicular multispecific organic anion transporter /multidrug resistance-associated protein 2 (cMOAT/MRP2) on both biliary excretion and intestinal exsorption of irinotecan hydrochloride (CPT-11) and its metabolite, SN-38, in the lactone and carboxylate forms. Cyclosporin A (CsA) was used to modulate P-gp and cMOAT/MRP2. Methods. The transcellular transport of CPT-11 and SN-38 was examined by using LLC-PK1 derivative cell lines transfected with murine mdr1a both in the absence or in the presence of CsA. The excretions of the compounds through the biliary and intestinal membrane routes were investigated by in situ perfusion technique. Results. Basolateral-to-apical transport of CPT-11 lactone in L-mdr1a cells was significantly decreased by CsA (10 μM). The trans- cellular transport of SN-38 lactone showed similar behaviors as those of CPT-11 lactone. The biliary excretion and the intestinal exsorption of both forms of CPT-11 and SN-38 were significantly inhibited when the drug was co-administered with CsA. Conclusions. The transports of CPT-11 and SN-38 via the biliary route seem to be essentially related with cMOAT/MRP2, whereas those of both compounds via the intestinal membrane seem to be related with P-gp.

Transient inhibition of CYP3A in rats by star fruit juice

Star fruit juice is a potent in vitro inhibitor of CYP3A; however, few reports are available on the inhibition of CYP3A activities by star fruit juice in vivo. Therefore, in this study, we investigated the CYP3A-mediated star fruit-drug interaction in vivo. The effect of star fruit juice on carbamazepine pharmacokinetics was examined in rats. In comparison with water, the area under the concentration-time curve (AUC) of carbamazepine was approximately 1.3-fold greater when star fruit juice (2 ml) was orally administered 1 h before the oral administration of carbamazepine (50 mg/kg). In contrast, the elimination half-life of carbamazepine and the AUC ratio of carbamazepine 10,11-epoxide to carbamazepine were not altered by the administration of star fruit juice. These results suggest that star fruit juice impairs the function of enteric CYP3A, but not of hepatic CYP3A. In addition, we evaluated the time course of recovery of CYP3A activity that was reduced after the treatment with star fruit juice. The inhibition by star fruit juice was recovered within approximately 24 h. These data suggest that the effect of star fruit juice is mainly reversible and transient. Thus, we discovered that star fruit juice alters the carbamazepine pharmacokinetics in rats.

Adrenomedullin increases phosphatidylcholine secretion in rat type II pneumocytes

Adrenomedullin, a novel hypotensive peptide, has been reported to be produced in the lung as well as in the adrenal medulla. However, the effect of adrenomedullin on lung function is still poorly understood. In this study, we detected the expression of both adrenomedullin mRNA and putative adrenomedullin receptor mRNA in primary cultures of rat type II pneumocytes. Adrenomedullin increased the secretion of phosphatidylcholine, the predominant component of pulmonary surfactant, by type II pneumocytes. The increase was partly inhibited by pretreatment with the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37). Furthermore, the increased phosphatidylcholine secretion was significantly inhibited by several protein kinase C inhibitors, such as sphingosine, 2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]3-(1H-indol-3-yl) maleimide (Gö6983), 3-[1-(3-amidinothio)-propyl-1H-indoyl-3-yl]3-(1-methyl-1H-++ +indoyl-3-yl ) maleimide methane sulfonate (Ro-31-8220), and staurosporine. Our results suggest that adrenomedullin can be considered a candidate autocrine modulator of surfactant secretion in type II pneumocytes.

Analysis of CYP3A inhibitory components of star fruit (Averrhoa carambola L.) using liquid chromatography–mass spectrometry

In this study, we analyzed the CYP3A inhibitory components of star fruit Averrhoa carambola L., using liquid chromatography–mass spectrometry (LC–MS). The stereoisomer of procyanidin B1 and B2 and/or the trimer consisting of catechin and/or epicatechin were suggested to be potent inhibitory components.

Hyuganatsu Orange (Citrus tamurana Hort. Ex Tanaka) Contains a Water Soluble Substance That Suppresses Bone Loss in Ovariectomized Rats

We investigated whether Hyuganatsu orange (Citrus tamurana Hort. ex Tanaka) contains water and acetic-acid soluble substances that increase bone mineral density (BMD) in ovariectomized rats. In in vivo study, femoral BMD can significantly increased. In in vitro study, tartrate-resistant acid phosphatase (TRAP) positive cells significantly decreased. We speculate that Hyuganatsu orange contains biologically active substances other than hesperidin that increase BMD.

Change in Drug Concentration in Serum Stored in Sterilized Vacuum Tubes for Serum Separation

We investigated the change in drug concentrations in serum stored in sterilized vacuum tubes for serum separation. The serum concentrations of seven drugs-phenytoin, phenobarbital, carbamazepine, vancomycin, valproate, theophylline and digoxin-were determined after storage in three different vacuum tubes-Vacutainer® SST and SST II (SST, SST II, Becton Dickinson Co. Ltd.) and Neo-Tube® GP-SP 1029 (GP-SP, Nipro Co.). Though there was no change in the serum drug concentrations for any of the tested drugs in GP-SP, the concentrations of phenytoin, phenobarbital and carbamazepine in the serum stored in SST and SST II were significantly decreased due to adsorption onto the serum separator. The degree of adsorption was greater for the SST tube than the SST II tube and for the drugs, the order of adsorption was phenytoin>carbamazepine>phenobarbital. The adsorption of phenytoin onto the separator of SST depended on several storage conditions, such as initial drug concentration, storage temperature and storage volume, while its adsorption onto the SST II separator depended on storage temperature and storage volume. In addition, the change in phenytoin concentration during storage in the SST tube was well correlated with the free fraction of the drug. This indicates that protein binding is an important factor affecting the stability of drug concentrations in serum stored in separation tubes. Overall, the results of our study indicate that for accurate therapeutic drug monitoring, it is necessary to select vacuum serum separation tubes on the basis of drug concentration stability data for them.