Investigation of actual use of laxatives and application to the active drug information offer in drug control guidance

金沢大学医学部附属病院薬剤部On the therapy of constipation, there are few reports that surveyed the actual circumstance of patients taking laxatives and the effectiveness of the drug. In this study, we investigated the contents in prescription, the actual conditions of administration of laxatives, and the subjective symptoms of inpatients in all wards of Kanazawa University hospital (2000. 12.1-2000. 12. 10). As a result of the investigation, the percentage of patients prescribed some laxatives was found to be about 31.5% (274) of all hospitalized patients (871), and among them about 16% (43) of the patients had some problems in defecation control. One of the causes leading to the problems for some patients (11) among them seemed to be due to the lesser amount of magnesium oxide taken per day. Then, in the ophthalmology ward we further investigated the proper use of laxatives and the defecation condition of the patient using a questionnaire paper and a record paper (20 cases). Patients became constipated by hospitalization, and although being administered some laxatives, they were often insufficient to control the defecation. Some patients (7) with changeable defecation control could be improved by change or addition of prescription. Pharmacist concerned 5 cases of patients with change or addition of prescription. This study indicates that pharmacists should actively offer information and rational usage of laxatives to doctors and patients

Obesity-induced increase of CYP2E1 activity and its effect on disposition kinetics of chlorzoxazone in Zucker rats

金沢大学医学部附属病院薬剤部This study was designed to investigate the induction of CYP2E1 in obese Zucker rats and its effect on the disposition kinetics of chlorzoxazone (CZX). CZX 20 mg/kg was administered to three groups of rats: normal Zucker rats fed a normal diet (ND), normal Zucker rats fed a high-fat diet (HF), and genetically obese Zucker rats fed a normal diet (OB). The values of the area under the plasma concentration–time curve from 0 to 1 (AUC1) of CZX were in the order of ND > HF > OB rats. The AUC1 values of total 6-hydroxychlorzoxazone (6OHCZX-T), which is considered to be a CYP2E1 metabolic marker, were in the opposite order. The values of the AUC1 ratio (6OHCZX–T/CZX) in ND, HF and OB rats were approximately 0.2, 0.3 and 0.4, respectively. The CZX concentration in fat was much higher than the concentrations in plasma, liver and kidney in all groups. Induction of CYP2E1 protein was greater in both liver and fat of OB rats than in those of HF rats. Microsomal activity of CYP2E1 in liver and fat was also in the order of OB > HF > NMrats. These results suggest that CYP2E1 may be induced in liver and fat of obese patients, thereby potentially altering the disposition kinetics of not only CZX, but also other lipophilic drugs metabolized by CYP2E1.©2006 Published by Elsevier Inc

Studies on the mechanism of subcellular distribution of basic drugs based on their lipophilicity

金沢大学医学部附属病院薬剤部This paper described the studies on the mechanism of subcellular distribution of lipophilic weak bases. Although the tissue distribution of basic drugs appeared to decrease with time simply in parallel with their plasma concentration, their subcellular distribution in various tissues exhibited a variety of patterns. Basic drugs were distributed widely in various tissues, but were concentrated in lung granule fraction, where their accumulation was dependent on their lipophilicity and lysosomal uptake. As the plasma concentration of drugs decreased after maximum level, the contribution of lysosomes to their subcellular distribution increased. The uptake of the basic drugs into lysosomes depended both on their intralysosomal pH and on the drug lipophilicity. As the lipophilicity of the basic drugs increased, they accumulated more than the values predicted from the pH-partition theory and raised the intralysosomal pH more potently, probably owing to their binding with lysosomal membranes with or without additional intralysosomal aggregation. These phenomena should be considered as a basis of drug interaction in clinical treatments

Selective drug delivery to bone using acidic oligopeptides

金沢大学附属病院薬剤

Bone-targeting of quinolones conjugated with an acidic oligopeptide

Purpose. Osteomyelitis is a progressive infectious process resulting in inflammatory destruction and necrosis of bone. The long-term administration of high-dosage antibiotics is required to treat osteomyelitis, owing to the limited distribution of antibiotics within bone. Therefore, targeted delivery of antibiotics to bone promises to improve therapeutic effectiveness. Methods. We synthesized quinolones such as levofloxacin and norfloxacin conjugated to an acidic oligopeptide, which works as a bone-targeting carrier after systemic administration. The therapeutic effectiveness of the conjugated quinolones in osteomyelitis was evaluated using a mouse model of osteomyelitis, created by inoculating Staphylococcus aureus into the tibia of mice. Results. With intravenous injection, the conjugated quinolones selectively distributed to bone, reaching concentrations up to 100-fold those of non-conjugated quinolones. Single intravenous injection of levofloxacin as well as conjugated levofloxacin exhibited antibiotic effects in the osteomyelitis mouse model; conversely, neither conjugated nor non-conjugated norfloxacin was effective. The antibiotic effect of conjugated levofloxacin persisted to at least 6 days after injection, whereas the effect of non-conjugated levofloxacin was temporary. Conclusion. The selective bone delivery of quinolones conjugated with an acidic oligopeptide may be effective in treating osteomyelitis, although the resulting concentration of antibiotic may be insufficient to completely kill S. aureus. © 2008 Springer Science+Business Media, LLC

Influence of chronic hepatic failure on disposition kinetics of valproate excretion through a phase II reaction in rats treated with carbon tetrachloride

The influence of chronic hepatic failure on the disposition kinetics of valproate (VPA) excretion via a phase II reaction was examined in rats treated with carbon tetrachloride (1.0 mg/kg, s.c., 3 times a week) for 2 or 3 months. There was no significant difference in the plasma concentration-time courses of VPA among the control and two treated groups up to 120 min after i.v. administration of VPA (75 mg/kg), but subsequently the plasma concentrations of the treated groups declined significantly below the control levels. Expression of Mrp2 mRNA in the liver of the treated groups was significantly lower than in the control group; conversely that in the kidney was significantly higher. The enzyme activity of UGTs in the liver of the treated groups decreased significantly, but UGT1A8 mRNA expression in the duodenum was increased about 3-fold. Cumulative excretion of VPA glucuronide (VPA-G) in bile of the treated groups was reduced significantly, while that in urine was markedly increased. In conclusion, the area under the VPA plasma concentration-time curve was decreased significantly in rats with chronic hepatic failure owing to increased excretion of VPA-G via the kidney as a result of induction of Mrp2, and inhibition of enterohepatic circulation of VPA-G. Copyright © 2007 John Wiley & Sons, Ltd

Inhibition of epidermal growth factor-induced cell transformation and Akt activation by caffeine

金沢大学医学部附属病院薬剤部We found that caffeine significantly inhibited epidermal growth factor (EGF)- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation in the JB6 mouse epidermal cell line. The tumor promoter-induced cell transformation was also blocked by treatment with an adenosine A1 receptor antagonist, 8-phenyltheophylline (8-PTH). Caffeine slightly attenuated activation of EGF-induced activator protein 1 (AP-1) activation, which play important roles in cell transformation, but only at the highest concentration examined (1 mM). Interestingly, pretreatment with caffeine suppressed EGF-induced phosphorylation and activation of Akt and ribosomal p70 S6 protein kinase (p70 S6K), a target of Akt, without inhibiting phosphatidylinositol 3-kinase (PI3K) activation. The inhibition of Akt activation of caffeine was not a result of its adenosine receptor antagonism. Because Akt plays a key role in signal transduction pathways leading to cell proliferation and apoptosis, our results provide novel insight into possible mechanisms of the chemotherapeutic effect of caffeine. © 2005 Wiley-Liss, Inc

Structure-activity relationship of flavonoids for inhibition of epidermal growth factor-induced transformation of JB6 CI 41 cells

金沢大学医学部附属病院薬剤部We found that quercetin, myricetin, quercetagetin, fisetin, (-)-epigallocatechin gallate (EGCG), and theaflavins, among 24 flavonoids examined, markedly inhibited epidermal growth factor (EGF)-induced cell transformation of mouse epidermal JB6 Cl 41 cells. The six flavonoids suppressed the EGF-induced activation of activator protein 1 (AP-1). In addition, myricetin, quercetagetin, EGCG, and theaflavins directly inhibited EGF-induced phosphatidylinositol 3-kinase (PI3K) activation. The important structural features of flavonoids for cell transformation-inhibitory activity are 3′- and 4′-OH on the B-ring, 3-OH on the C-ring, C2=C3 double bond in the C-ring, and the phenylchromone (C6-C5-C6) skeleton in the flavonols, and the galloyl group in EGCG and theaflavins. Our results provide new insight into possible mechanisms of the anti-carcinogenic effects of flavonoids, and could help to provide a basis for the design of novel cancer chemopreventive agents. © 2007 Wiley-Liss, Inc

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

金沢大学医学部附属病院薬剤部We examined whether the oral bioavailability of cyclosporin A is controlled primarily by P-glycoprotein (P-gp) or CYP3A in the small intestine. In situ loop method was used to evaluate the uptake of cyclosporin A (40 nmol) at the upper and lower intestine of wild-type and mdr1a/1b knockout mice treated or not treated with dexamethasone (75 mg/kg/day, 7 days, i.p.). Expression of CYP3A mRNA in the control group was higher in the upper than the lower intestine, while that of the multidrug resistance-1a (mdr1a) mRNA was in the opposite order. Dexamethasone administration potently induced CYP3A and mdr1a mRNAs in the lower and upper intestine, respectively. At 45 min after cyclosporin A administration into an upper intestinal loop of the control group of wild-type mice, the ratio of residual cyclosporin A to dose did not differ significantly from that of mdr1a/1b knockout mice, whereas in dexamethasone-treated wild-type mice, the residual ratio was increased significantly. The ratio of the cyclosporin A metabolite M17 to cyclosporin A in portal venous blood at an upper intestinal loop of mdr1a/1b knockout mice was much higher than that a lower intestinal loop. The M17/cyclosporin A ratio of portal venous blood at a lower intestinal loop in mdr1a/1b knockout mice was increased significantly by dexamethasone treatment. These results suggest that, under physiological conditions, the oral bioavailability of cyclosporin A is mainly controlled by CYP3A in the upper intestine, rather than liver, but when P-gp is induced by steroid, the intestinal absorption of cyclosporin A may be inhibited. © 2006 Elsevier Inc. All rights reserved

Mechanism of decrease of oral bioavailability of cyclosporin a during immunotherapy upon coadministration of amphotericin B

金沢大学附属病院薬剤部The trough level of blood concentration of cyclosporin A (CyA) in a patient receiving immunotherapy was observed to decrease following coadministration of amphotericin B (AMB). This clinical observation was confirmed experimentally in Wistar rats intravenously given AMB (1.5 or 3.0 mg/kg) or saline (control) for 4 days, followed by CyA (10 mg/kg). The blood concentration of CyA after i.v. or p.o. administration in both AMB groups was significantly decreased compared with the control. The oral bioavailability of CyA after 1.5 or 3.0 mg/kg AMB treatment was decreased to 67% or 46%, respectively, of that of the control group. AMB treatment increased the expression levels of mdr1a and mdr1b mRNAs in the duodenum to about three times the control, and expression of CYP3A2 mRNA in the liver was increased to about twice the control. The P-gp and CYP3A2 proteins were increased significantly. These findings suggest that the oral bioavailability of CyA is reduced as a result of both increased efflux transport via P-glycoprotein in the duodenum and an increased first-pass effect of CYP3A2-mediated hepatic metabolic activity, induced by AMB. It is suggested that careful monitoring of CyA levels is necessary in the event of AMB administration to patients receiving immunotherapy with CyA. Copyright © 2008 John Wiley & Sons, Ltd