Hiroki Konishi

Effect of fluconazole on theophylline disposition in humans

The effect of fluconazole, an antimycotic that inhibits cytochrome P-450-mediated drug metabolism, on theophylline kinetics and the production of its metabolites were compared with those of enoxacin in 5 healthy subjects. All subjects received a single oral dose of 240 mg theophylline (aminophylline, 300 mg) after they had been given oral fluconazole 100 mg every 12 h or enoxacin 200 mg every 8 h for three consecutive days.Pretreatment with enoxacin decreased the total clearance (CLT) and elimination rate constant (Kel) of theophylline by 50% and 46%, respectively, without changing the volume of distribution (Vd), but there were no significant change in any pharmacokinetic parameter when fluconazole was administered. Enoxacin led to a 50% reduction in the metabolic clearance (CLM) of theophylline and to decreases of 69%, 59% and 38% in the formation clearance of the three theophylline metabolites, 3-methylxanthine (3-MX), 1-methyluric acid (1-MU), and 1,3-dimethyluric acid (1,3-DMU), respectively, accompanied by significant changes in the urinary recovery of theophylline and its metabolites. In contrast, treatment with fluconazole led only to a slight decrease in the CLM of theophylline (16%) and in the formation clearance of its metabolites (15%–18%), and there was no change in the renal clearance (CLR) of theophylline.The results indicate that fluconazole is a minor inhibitor of theophylline disposition compared with enoxacin, and they suggest that the inhibitory action of fluconazole is selective for certain cytochrome P-450 isozymes, but not for the cytochrome P-4501A involved in theophylline metabolism.

Predictive performance of serum digoxin concentration in patients with congestive heart failure by a hyperbolic model based on creatinine clearance

Objectives:  To formulate a simple equation for determining the daily dose requirements of digoxin by inclusion of creatinine clearance (Ccr) values as an explanatory variable.

Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses.

The organ toxicity of doxorubicin (DOX), an anthracycline antineoplastic agent, narrows the therapeutic window despite its clinical usefulness. In the present study, we determined whether taurine protected against DOX-induced hepatic injury, and explored the molecular mechanisms underlying the suppressive effects of taurine in terms of alterations in oxidative stress and apoptotic responses. DOX-induced body weight loss was completely suppressed by taurine treatment. Elevations in the serum activity levels of lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase by DOX were also dose-dependently attenuated by a concurrent treatment with taurine. Superoxide dismutase activity and reduced glutathione content in the liver were decreased following the administration of DOX, whereas these changes were suppressed when 10 mg/kg taurine was given in combination with DOX. Taurine attenuated the increased expression of mRNAs for Fas and Bax after DOX exposure. Furthermore, the formation of cleaved caspase-3 protein in the group given DOX with taurine was lower than that in the group treated with DOX alone. Our results suggest that taurine can protect against DOX-induced acute hepatic damage, the underlying mechanism of which is attributable to the suppression of oxidative stress and apoptotic responses.

Theanine prevents doxorubicin-induced acute hepatotoxicity by reducing intrinsic apoptotic response.

Doxorubicin (DOX) is widely used as an antitumor agent with topoisomerase II inhibiting activity; however, its dosage and duration of administration have been strictly limited due to dose-related organ damage. The present study investigated whether theanine, an amino acid found in green tea leaves, could reduce DOX-induced acute hepatotoxicity and the apoptotic response in mice. Activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum, biomarkers of hepatic impairment, were markedly increased after the administration of 20 mg/kg DOX, whereas the degree of these elevations was significantly attenuated by 10 mg/kg theanine, which was consistent with histological hepatic images assessed by microscopic examination. The hepatic expression of Bax and Fas, representative intrinsic and extrinsic apoptotic molecules, respectively, was significantly increased by dosing with DOX. However, the elevation in the hepatic expression of Bax, but not Fas, was suppressed to control levels by theanine. The formation of cleaved caspase-3 protein in the group given DOX with theanine was significantly lower than that in the group treated with DOX alone. These results suggest that theanine can protect against acute hepatic damage induced by DOX, which is attributed to the suppression of intrinsic caspase-3-dependent apoptotic signaling.

Probable Metabolic Interaction of Doxifluridine with Phenytoin

OBJECTIVE: To report the marked elevation of the serum phenytoin concentration during treatment with antineoplastic agents. CASE SUMMARY: A 51-year-old Japanese woman, who was diagnosed with multiple brain metastatic tumors, was placed on oral phenytoin at a maintenance dose of 200 mg/d (3.8 mg/kg/d) to prevent seizures. The serum concentration of phenytoin was well controlled within the therapeutic range; no seizures occurred. Four months later, combination therapy with doxifluridine (5′-DFUR) 800 mg/d, cyclophosphamide 100 mg/d, and medroxyprogesterone acetate 800 mg/d was initiated because of further metastasis. Approximately 1 month after the start of concurrent treatment with the antineoplastic agents, the serum phenytoin concentration was elevated to fourfold of the original concentration. Staggering was observed at that time, but toxic symptoms gradually subsided with the decline in the serum phenytoin concentration after its withdrawal. DISCUSSION: A probable explanation for the marked elevation of serum phenytoin concentration is a reduction of the capacity of CYP2C-dependent phenytoin metabolism, and the antineoplastic agents could be involved in this event. The interaction of fluorouracil and phenytoin is known in clinical practice, and it is reported that the expression of hepatic CYP2C enzymes is depressed by exposure of rats to fluorouracil. 5′-DFUR, a prodrug of fluorouracil, was considered the likeliest candidate responsible for the interaction. This interaction was of clinical significance because of the great extent of changes in the serum phenytoin concentration. CONCLUSIONS: Clinicians should be aware of the elevation of serum phenytoin concentrations when phenytoin is given in combination with fluorouracil derivatives, including 5′-DFUR.

Decrease in oral bioavailability of ciclosporin by intravenous pulse of methylprednisolone succinate in rats.

We examined the effects of high‐dose methylprednisolone on the bioavailability of orally administered ciclosporin in rats. To emulate the clinical protocol of methylprednisolone pulse therapy, methylprednisolone sodium succinate (MPS), a prodrug of methylprednisolone, was intravenously administered as repeated doses (66.3 mg kg−1) for 3 days. The area under the blood ciclosporin concentration versus time curve after oral administration was significantly reduced by 60% by pulse treatment with MPS. Based on our previous finding that the total body clearance of ciclosporin was reduced by about 20% by the same methylprednisolone pulse protocol, the extent of reduction in the oral bioavailability of ciclosporin was estimated to be approximately 50%, indicating a drug interaction between high‐dose methylprednisolone and orally administered ciclosporin, which affected the absorption process. In rats treated with MPS, an in‐situ efflux experiment using rhodamine‐123 demonstrated that the reverse transport function of P‐glycoprotein (P‐gp) in the small intestine was significantly enhanced, although there was no significant increase in the intestinal microsomal activity of triazolam α‐ and 4‐hydroxylation, metabolic probes for CYP3A. In addition, a significant decrease was observed in the amount of secreted bile acids serving as an enhancer of gastrointestinal absorption of ciclosporin in MPS treatment. To directly estimate the absorptive capacity, an in‐situ absorption test was conducted using a closed‐loop of small intestine in control and MPS‐treated rats. Intestinal absorption of ciclosporin was significantly decreased, not only in the absence of bile flow but also by treatment with MPS, which well reflected the change in the in‐vivo pharmacokinetic behaviour of ciclosporin after methylprednisolone pulsing. These results demonstrate that bioavailability of ciclosporin is markedly reduced by MPS pulse treatment, and the mechanism of this interaction was confirmed to involve enhancement of small‐intestinal P‐gp function and decrease in bile secretion.

Depression of phenytoin metabolic capacity by 5-fluorouracil and doxifluridine in rats.

It has been found in clinical practice that the serum level of phenytoin, of which metabolism is mediated by hepatic CYP2C enzymes, was markedly elevated by co‐administration of 5‐fluorouracil (5‐FU) and doxifluridine (5′‐deoxy‐5‐fluorouridine; 5′‐DFUR), a prodrug of 5‐FU, but the detailed mechanisms are unclear. A study using rats was undertaken to examine the effects of 5‐FU and 5′‐DFUR on phenytoin metabolism in hepatic microsomes and phenytoin pharmacokinetics in‐vivo. Neither 5‐FU nor 5′‐DFUR exhibited direct inhibitory effects on hepatic microsomal phenytoin p‐hydroxylation, a major metabolic route catalysed by CYP2C in rats, as in humans. 5‐FU and 5′‐DFUR were injected intraperitoneally into male rats as single doses (1.68 mmol kg−1) and repeated doses (0.24 mmol kg−1 for 7 days). Control rats received vehicle alone. A significant reduction in the activity of phenytoin p‐hydroxylation was observed 4 days after the last administration irrespective of the agents and their treatment regimens, although the activity was unchanged on Day 1. Pharmacokinetic analysis of phenytoin revealed that the elimination rate constant and the total clearance was decreased by 70–75 % in both the 5′‐DFUR‐treated and 5‐FU‐treated rats, indicating that the decrease in the metabolic capacity of phenytoin was responsible for the change in phenytoin disposition in‐vivo. On the other hand, 5‐FU significantly depressed the total P450 content, NADPH cytochrome c reductase activity and activities of progesterone hydroxylations. However, the depressive effects of 5′‐DFUR were not very potent relative to those of 5‐FU, which can be explained by the fact that 5‐FU is derived from 5′‐DFUR to only a small extent. According to a recent report, phenytoin p‐hydroxylation and progesterone 2α‐/21‐hydroxylations share common CYP2C enzymes as their catalysts. Because there was a difference in the modulation profiles between phenytoin p‐hydroxylation and progesterone 2α‐/21‐hydroxylations after exposure to 5′‐DFUR, 5′‐DFUR might modulate phenytoin metabolism without loss of catalytic ability for other substrates, unlike 5‐FU. The present study suggested that the down‐regulation of hepatic CYP2C enzymes occurs by 5‐FU exposure even at a low level, and provided a fundamental explanation for the drug interaction encountered in clinical practice.

Reduction of Opioid Side Effects by Prophylactic Measures of Palliative Care Team May Result in Improved Quality of Life

PURPOSE In February 2002, the palliative care team was established in Ikeda Municipal Hospital to improve palliative care. We investigated changes in the incidences of side effects related to opioids, and evaluated palliative care team activities. METHODS Regarding inpatients for whom narcotics were prescribed in our hospital in the years of 2002 (from October 1, 2002 until September 30, 2003), 2004 (from October 1, 2004 until September 30, 2005), and 2006 (from October 1, 2006 until September 30, 2007), we surveyed the rates at which laxatives or antiemetics were prescribed, frequency of defecation/its state before and after the start of narcotic therapy, frequency of nausea/vomiting, and dietary intake. RESULTS The proportions of patients in whom laxatives were simultaneously prescribed during opioid therapy in 2002, 2004, and 2006 were 43.5%, 78.7%, and 75.6%, respectively. The proportions of those in whom antiemetics were combined with opioids were 45.7%, 78.7%, and 78.0%, respectively. The incidences of constipation were 50.0%, 39.3%, and 37.8%, respectively. Those of nausea/vomiting were 30.4%, 21.3%, and 9.8%, respectively. Those of anorexia were 65.3%, 39.4%, and 15.4%, respectively. CONCLUSIONS These results suggest that palliative care team activities facilitated appropriate drug prescription during opioid therapy, reducing the appearance of side effects, with likelihood of improved quality of life.

Increased Gene Expression of Glucose Transporters in the Mouse Brain after Treatment with Fluoxetine and Pergolide

Glucose transporters play key roles in the homeostatic control of brain functions. In the present study, we examined the effect of fluoxetine, a selective serotonin reuptake inhibitor, and pergolide, a dopamine D receptor agonist, on the gene expression levels of glucose transporters in the mouse brain. mRNAs for 8 sodium-independent glucose transporters (GLUTs), other than GLUT4 and GLUT9, and sodium-dependent glucose transporter 1 (SGLT1) were confirmed to be expressed in brain tissue. Fluoxetine and pergolide significantly increased the expression levels of mRNAs for GLUT1 and GLUT10 in the brain. Furthermore, the expression of GLUT6 in tissue was increased by administering pergolide to mice. On the other hand, fluoxetine and pergolide had no effect on the expression levels of mRNAs for the other GLUTs and SGLT1. Therefore, we concluded that the gene expression of several GLUT isoforms in the mouse brain was affected by the treatment with fluoxetine and pergolide.

Influence of intravenous methylprednisolone pulse treatment on the disposition of ciclosporin and hepatic CYP3A activity in rats.

We examined the effects of high‐dose methylprednisolone (MP) on the disposition of ciclosporin (CsA) and hepatic microsomal CYP3A activity using rats. Methylprednisolone sodium succinate (MPS), a prodrug of MP, was intravenously administered as repeated doses (66.3 mg kg−1) for 3 days or as a single dose. In MP‐treated rats, a significant increase was observed in the total body clearance (CLtot) and elimination rate constant (Ke) of intravenously administered CsA. The enzyme activities of triazolam hydroxylations and erythromycin N‐demethylation in hepatic microsomes were also enhanced by about 50% by MP treatment, suggesting that the alteration in the CsA pharmacokinetics was due to significant induction of the hepatic CYP3A responsible for the metabolic conversion of CsA. In contrast, no significant changes in the values of CLtot and Ke were found following a single treatment with MP. On the other hand, MP inhibited the CYP3A‐mediated triazolam hydroxylations in a concentration‐dependent manner. The difference between the in‐vivo and in‐vitro inhibitory behaviours of MP was attributed to the rapid elimination of MP after biotransformation from MPS because the plasma MP concentration decreased with a half‐life of 15 min immediately after reaching a level close to the inhibition constant for the triazolam 4‐hydroxylation reaction (32.4 μm). Although there is a general consideration that MP cannot act as an enzyme inducer at maintenance doses, the present results strongly suggest that high‐dose MP is likely to interact pharmacokinetically with CsA by inducing hepatic CYP3A. These results may provide basic explanations for the clinical experience that blood CsA levels are reduced during MP pulse therapy.