Absorption, disposition and metabolic pathway of amiselimod (MT-1303) in healthy volunteers in a mass balance study.

The absorption, metabolism and excretion of MT-1303 were investigated in healthy male subjects after a single oral dose of 0.4 mg [14C]-MT-1303 (ClinicalTrials.gov NCT02293967). The MT-1303 concentration in the plasma reached a maximum at 12 h after administration. Thereafter, the concentration declined with a half-life of 451 h. At the final assessment on Day 57, 91.16% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 35.32% and 55.84%, respectively. The most abundant metabolite in plasma was MT-1303-P, which accounted for 42.6% of the area under the plasma concentration-time curve (AUC) of the total radioactivity. The major component excreted in urine was Human Urine (HU)4 (3066434), accounting for 28.1% of radioactivity in the sample (4.05% of the dose), whereas MT-1303 was a major component in the faeces, accounting for 89.8% of radioactivity in the sample (25.49% of the dose) up to 240 h after administration. This study indicates that multiple metabolic pathways are involved in the elimination of MT-1303 from the human body and the excretion of MT-1303 and MT-1303-P via the kidney is low. Therefore, MT-1303 is unlikely to cause conspicuous drug interactions or alter pharmacokinetics in patients with renal impairment.

Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

AIMS: Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. METHODS: Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18-55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18-55 years), 25, 50, 100 and 150 mg (Japanese males, 18-55 years). Study 2: Caucasian males (18-55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21-28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests. RESULTS: Peak TA-8995 concentrations occurred approximately 4 h post-dose. Mean half-lives ranged from 81 to 166 h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92-99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated. CONCLUSIONS: TA-8995 is a potent CETP inhibitor and warrants further investigation.

Metabolism and disposition of the dipeptidyl peptidase IV inhibitor teneligliptin in humans.

1. The absorption, metabolism and excretion of teneligliptin were investigated in healthy male subjects after a single oral dose of 20 mg [(14)C]teneligliptin. 2. Total plasma radioactivity reached the peak concentration at 1.33 h after administration and thereafter disappeared in a biphasic manner. By 216 h after administration, ≥90% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 45.4% and 46.5%, respectively. 3. The most abundant metabolite in plasma was a thiazolidine-1-oxide derivative (designated as M1), which accounted for 14.7% of the plasma AUC (area under the plasma concentration versus time curve) of the total radioactivity. The major components excreted in urine were teneligliptin and M1, accounting for 14.8% and 17.7% of the dose, respectively, by 120 h, whereas in faeces, teneligliptin was the major component (26.1% of the dose), followed by M1 (4.0%). 4. CYP3A4 and FMO3 are the major enzymes responsible for the metabolism of teneligliptin in humans. 5. This study indicates the involvement of renal excretion and multiple metabolic pathways in the elimination of teneligliptin from the human body. Teneligliptin is unlikely to cause conspicuous drug interactions or changes in its pharmacokinetics patients with renal or hepatic impairment, due to a balance in the elimination pathways.

Effect of Hepatic and Renal Impairment on the Pharmacokinetics of Dersimelagon (MT-7117), an Oral Melanocortin-1 Receptor Agonist.

Dersimelagon is an orally administered selective melanocortin-1 receptor agonist being investigated for treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis. Dersimelagon is extensively metabolized in the liver, and potential recipients may have liver dysfunction. Further, effects of renal impairment on pharmacokinetic properties should be established in drugs intended for chronic use. Two separate studies (ClinicalTrials.gov: NCT04116476; NCT04656795) evaluated the effects of hepatic and renal impairment on dersimelagon pharmacokinetics, safety, and tolerability. Participants with mild (n = 7) or moderate (n = 8) hepatic impairment or normal hepatic function (n = 8) received a single oral 100-mg dersimelagon dose. Participants with mild (n = 8), moderate (n = 8), or severe (n = 8) renal impairment or normal renal function (n = 8) received a single 300-mg dose. Systemic exposure to dersimelagon was comparable with mild hepatic impairment but higher with moderate hepatic impairment (maximum observed plasma concentration, 1.56-fold higher; area under the plasma concentration-time curve from time 0 extrapolated to infinity, 1.70-fold higher) compared with normal hepatic function. Maximum observed plasma concentration and area under the plasma concentration-time curve from time 0 extrapolated to infinity were similar with moderate renal impairment but higher with mild (1.86- and 1.87-fold higher, respectively) and severe (1.17- and 1.45-fold higher, respectively) renal impairment versus normal renal function. Dersimelagon was generally well tolerated.

Evaluation of Age-Related Changes in Teneligliptin Pharmacokinetics in Japanese and European Descent Subjects Using a Physiologically Based Pharmacokinetic Model.

INTRODUCTION: Drugs often show differing pharmacokinetic (PK) profiles, such as higher plasma concentrations, in older people than in younger people owing to age-related decreases in physiological functions. However, it is difficult to evaluate the PK in older populations. Therefore, we simulated the plasma age-related changes in the PK of teneligliptin, a dipeptidyl peptidase-4 inhibitor, using physiologically based PK (PBPK) models. METHODS: The previously developed PBPK model was revalidated by comparison between simulated data and clinical study data that included older subjects (up to 75 years old). We then simulated the plasma concentration-time profiles for teneligliptin at a dose of 20 mg (single and multiple doses) in virtual Japanese (20-70 years old) and European descent (20-98 years old) subjects. PK parameters were calculated by race and age group. RESULTS: We confirmed the validity of the previous PBPK model by comparison between simulated data and clinical study data. In the evaluation of age-related changes in PK after single and multiple doses using the PBPK model, the area under the plasma concentration-time curve (AUC) of teneligliptin tended to increase slightly with age in both populations up to 70 years old. However, no clear age-related change in the maximum plasma concentration (Cmax) of teneligliptin was observed. In the European descent subjects aged ≥ 70 years, the AUC tended to increase but the ratio of the change in Cmax was smaller than that in AUC. In both populations, there were positive correlations between AUC and age, but not between Cmax and age. CONCLUSION: The simulation using a PBPK model showed a tendency for the AUC of teneligliptin to increase with age, whereas Cmax was less affected by age than AUC.

Phase 1 Studies to Define the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone in Healthy Volunteers.

Apararenone is a long-acting, nonsteroidal mineralocorticoid receptor antagonist (MRA). The safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of single- and multiple-dose apararenone were assessed in 3 phase 1 randomized, double-blind studies in 223 healthy adults. Study 1 assessed the PK, safety/tolerability, and PD of single-dose apararenone (3.75-640 mg) and multiple-dose apararenone (10-40 mg/day on days 1-14, 320 mg loading dose on day 1 + 10 mg/day on days 2-14, or 40-320 mg loading dose on day 1 + 2.5-20 mg/day on days 2-14) in Caucasian and Black men and women. Study 2 assessed the PK and safety of single-dose apararenone (5-320 mg) in healthy Japanese men. Study 3 assessed the PK, PD, and safety/tolerability of single-dose apararenone (160 or 640 mg) or eplerenone (200 mg; only for 160 mg of apararenone), each after fludrocortisone challenge in Caucasian men. In studies 1 and 2, an approximately dose-proportional increase was observed in PK parameters over the apararenone dose range of 3.75-40 mg; at higher doses, a less than dose-proportional increase was observed. Food, sex, age, and race had no apparent effect on apararenone PK. A long half-life was seen for apararenone and its principal metabolite; in addition, the exposure of the metabolite was lower than that of apararenone. Apararenone suppressed the decrease in urinary sodium and potassium ion ratio that occurs after loading with fludrocortisone. These studies support the mechanism of action of apararenone as an MRA, and further clinical development is warranted.

Collaborations between Clinical Pharmacologists in Japan and in the United States - Report from the IQ CPLG and JPMA CPTF Meeting in Tokyo, Japan.

The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Clinical Pharmacology Leadership Group (CPLG) held its first meeting of Japan-based representatives at Astellas Pharma headquarters in Tokyo on October 1, 2019. The meeting was also attended by Japan Pharmaceutical Manufactures Association (JPMA) Clinical Pharmacology Task Force (CPTF) members. Overall, nearly 30 clinical pharmacologists representing 14 companies attended the event. The meeting met its goal of enhancing mutual understanding of each organization's activities. In a number of break-out sessions, participants identified scientific topics for potential future collaboration between JPMA CPTF and IQ CPLG.

Drug-Drug Interactions of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone With Midazolam, Warfarin, and Digoxin: A Phase 1 Studies in Healthy Volunteers.

PURPOSE: To characterize the clinical relevance of in vitro drug-drug interaction findings with apararenone (MT-3995), the effects of apararenone on the sensitive substrates of cytochrome P450 3A4 (midazolam) and 2C9 (warfarin), and P-glycoprotein (digoxin), were assessed through a series of studies conducted in healthy volunteers. METHODS: Three studies were conducted in 56 healthy adults. Study 1 investigated the effects of the administration of apararenone with midazolam; apararenone was administered on days 2 (320 mg) and days 3-15 (20 mg/d), and midazolam 2 mg, on days 1 and 15. Study 2 investigated the effects of the administration of apararenone with warfarin; apararenone was administered on days 8-11 (40 mg/d) and days 12-27 (10 mg/d), and warfarin 25 mg, on days 1 and 21. Study 3 assessed the effects of the administration of apararenone with digoxin; apararenone was administered on days 11 (160 mg) and days 12-28 (10 mg/d), and digoxin 0.5 mg, on days 1 and 24. Pharmacokinetic parameters included Cmax, AUC0-t, and AUC0-∞. The safety profile was evaluated based on adverse events from spontaneous reports and clinical findings. FINDINGS: After the administration of midazolam together with apararenone, compared with midazolam alone, the midazolam ± apararenone treatment ratios (90% CIs) of the geometric least squares (LS) mean Cmax, AUC0-t, and AUC0-∞ values were 1.263 (1.147-1.392), 1.342 (1.220-1.477), and 1.370 (1.225-1.534), respectively. After the administration of warfarin ± apararenone, the R-warfarin ± apararenone treatment ratios (90% CIs) of the geometric LS mean Cmax, AUC0-t, and AUC0-∞ values were 1.008 (0.934-1.089), 1.078 (1.029-1.129), and 1.110 (1.056-1.166). Corresponding values for S-warfarin were 1.025 (0.941-1.117), 1.024 (0.979-1.071), and 1.031 (0.984-1.080). After the administration of digoxin ± apararenone, the digoxin ± apararenone treatment ratios (90% CIs) of the geometric LS mean Cmax, AUC0-t, and AUC0-∞ values were 0.929 (0.789-1.093), 0.894 (0.797-1.033), and 0.887 (0.805-0.977), respectively. Treatment-emergent adverse events were generally of mild to moderate intensity, and no serious adverse events of any kind were reported. IMPLICATIONS: The findings from this analysis of data from healthy volunteers suggest minimal risk for potential drug-drug interactions between apararenone and other drugs that are likely to be used concurrently in patients. ClinicalTrials.gov identifier: NCT02531568.

A comparative pharmacokinetic study of recombinant human serum albumin with plasma-derived human serum albumin in patients with liver cirrhosis.

We conducted an open-label, parallel-group study of the high purity, mass-produced recombinant human serum albumin (rHSA), derived from the methylotrophic yeast Pichia pastoris, to compare pharmacokinetics and ensure bioequivalence with plasma-derived human serum albumin (pHSA) in 22 patients with liver cirrhosis. Both rHSA and pHSA groups enrolled 11 patients each, assigned according to predose serum albumin concentrations using the minimization method. Pharmacokinetic and safety profiles for 3-day repeated intravenous infusions at a daily dose of 25 g were evaluated for 8 days. Geometric mean AUC(0-168hr) (g.hr/dL) was 637.12 and 635.93 in the rHSA and pHSA groups, respectively, with a 90% confidence interval (CI) for the difference (92.9%-108.1%) lying within the bioequivalence range. The other major parameter, geometric mean C(max) (g/dL), was 4.16 and 4.19 in the rHSA and pHSA groups, respectively, with a 90% CI for the difference (92.7%-106.4%). The pHSA group presented with 3 adverse events: 1 case of insomnia, and 2 laboratory abnormalities with no serious adverse events. Results from this study show similar pharmacokinetic profiles following intravenous administration of 25g/day of rHSA and pHSA for 3 days, indicating bioequivalence.

Clearance of imidapril, an Angiotensin-converting enzyme inhibitor, during hemodialysis in hypertensive renal failure patients: comparison with quinapril and enalapril.

The dialyzability of imidaprilat, an active metabolite of the angiotensin-converting enzyme (ACE) inhibitor imidapril, was determined and compared with those of enalaprilat and quinaprilat in hypertensive patients on chronic hemodialysis. Imidapril (5 mg/d, n = 6), enalapril (2.5 mg/d, n = 6), or quinapril (2.5 mg/d, n = 6) was given for at least 8 weeks prior to the trial. During dialysis, enalaprilat, but not imidaprilat or quinaprilat, concentrations in both sides decreased significantly. Compared to enalaprilat, the dialyzabilities of imidaprilat and quinaprilat were significantly lower (dialyzer clearance [mL/min/m(2)]: enalaprilat, 41.8 +/- 7.4; imidaprilat, 19.0 +/- 7.8; quinaprilat, 8.9 +/- 1.3). The dialyzabilities of the 3 drugs were negatively correlated with their respective protein-binding rates. During hemodialysis, blood pressure did not change significantly in any group. These results suggest that imidapril provides good blood pressure control without a large fluctuation of drug concentration in hypertensive patients undergoing chronic hemodialysis.

Pharmacokinetic profile of edaravone: a comparison between Japanese and Caucasian populations.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) affects persons of all races, and there continues to be a need for effective therapies to treat the disease. OBJECTIVE: To compare the pharmacokinetics (PK) of edaravone between Japanese and Caucasian populations. METHODS: Data from five PK studies among Japanese and Caucasian healthy volunteers were pooled and evaluated. In population PK (PPK) modelling, compartment models and other models with linear elimination were evaluated for appropriateness. Covariate effects by race, sex, weight, and age were investigated to explain variability in PK parameters. Simulations of the final PPK model were performed using a virtual population based on ALS clinical trials. RESULTS: The analysis included 86 subjects. A three-compartment model with Michaelis-Menten plus linear elimination was selected as the best fit model. Race was statistically detected as a covariate for the second peripheral volume of distribution (V2), indicating a 26% increase for Caucasian subjects compared to Japanese subjects. However, based on simulation of PPK model for a virtual ALS population, the small difference of V2 was associated with a difference of Ctau around 1 ng/mL after infusion, which was minimal compared to Cmax of approximately 1000 ng/ml. CONCLUSION: The PPK analyses demonstrated no clinically relevant difference in the PK profiles of edaravone by race, sex, weight, or age.

Amiselimod, a novel sphingosine 1-phosphate receptor-1 modulator, has potent therapeutic efficacy for autoimmune diseases, with low bradycardia risk.

BACKGROUND AND PURPOSE: We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT-1303), a second-generation sphingosine 1-phosphate (S1P) receptor modulator, designed to reduce the bradycardia associated with fingolimod and other S1P receptor modulators. EXPERIMENTAL APPROACH: The selectivity of the active metabolite amiselimod phosphate (amiselimod-P) for human S1P receptors and activation of G-protein-coupled inwardly rectifying K+ (GIRK) channels in human atrial myocytes were assessed. Its cardiac distribution was determined in rats, and cardiovascular telemetry was assessed in monkeys. We also examined the pharmacokinetics, pharmacodynamics and safety of amiselimod in healthy humans. KEY RESULTS: Amiselimod-P showed potent selectivity for S1P1 and high selectivity for S1P5 receptors, with minimal agonist activity for S1P4 and no distinct agonist activity for S1P2 or S1P3 receptors and approximately five-fold weaker GIRK activation than fingolimod-P. After oral administration of amiselimod or fingolimod at 1 mg·kg-1 , the concentration of amiselimod-P in rat heart tissue was lower than that of fingolimod-P, potentially contributing to the minimal cardiac effects of amiselimod. A telemetry study in monkeys confirmed that amiselimod did not affect heart rate or ECG parameters. In healthy human subjects, peripheral blood lymphocyte counts gradually reduced over the 21 day dosing period, with similar lymphocyte count profiles with the highest doses by day 21, and no clinically significant bradycardia observed on day 1 or during the study. CONCLUSIONS AND IMPLICATIONS: Amiselimod exhibited potent therapeutic efficacy with minimal cardiac effects at the anticipated clinical dose and is unlikely to require dose titration.

Vitamin E-bonded hemodialyzer improves neutrophil function and oxidative stress in patients with end-stage renal failure.

We evaluated the biocompatibility of a newly developed vitamin E hemodialyzer (CL-EE; Terumo Co Ltd, Tokyo, Japan) by neutrophil function and oxidant stress in patients with end-stage renal failure in a randomized crossover study. Ten patients underwent hemodialysis using either the CL-EE or a control dialyzer membrane identical to the CL-EE except for vitamin E binding for 12 weeks in a crossover fashion after a 1-month washout period with hemophane membranes. White blood cell counts, serum oxidized low-density lipoprotein (Ox-LDL) levels, and malondialdehyde (MDA) levels during hemodialysis sessions were measured at the initiation and end of the CL-EE and control trials. Superoxide anion production by neutrophils just before and 4 hours after starting the session also was measured. Leukocytopenia at 1 hour after starting the session was detected to a similar extent in both membranes. However, the degree of reduction was less in the CL-EE trial after repeated use. Superoxide anion production by neutrophils just before a hemodialysis session was reduced after repeated use of the CL-EE membrane. Serum Ox-LDL levels increased, whereas serum MDA levels decreased during sessions to a similar extent in both trials. However, these parameters were significantly lower in the CL-EE trial after repeated use. Serum LDL concentrations significantly decreased with repeated use of the CL-EE membrane. These data suggest that repeated use of the CL-EE membrane for 3 months improves neutrophil function, oxidant stress, and LDL concentrations in patients with renal failure. This membrane may be useful to reduce the incidence of cardiovascular events in patients with renal failure.

Partial protective effect of Y-27632, a Rho kinase inhibitor, against hepatic ischemia-reperfusion injury in rats.

(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)-cyclohexanecarboxamide dihydrochloride (Y-27632), a Rho kinase inhibitor, has a suppressive effect on the functions of polymorphonuclear leukocytes. In this study, the influence of Y-27632 on ischemia-reperfusion injury of the liver was examined in rats. Y-27632 (3 mg/kg) or vehicle alone was intravenously injected into rats 60 min before occlusion. Blood samples were obtained for 48 h after reperfusion. At the end of the experiment, the hepatic content of myeloperoxidase, which reflects the number of polymorphonuclear leukocytes in liver tissues, was determined. The increases in serum hepatic aminotransferases and inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6] after reperfusion were partially, but significantly, inhibited by Y-27632. The increased hepatic myeloperoxidase content was significantly lowered by Y-27632. These results suggest that Y-27632 has a partial protective effect against hepatic ischemia-reperfusion injury through the suppression of polymorphonuclear leukocytes and inflammatory cytokines.

SOFA score predicts postoperative outcome of patients with colorectal perforation.

BACKGROUND/AIMS: Colorectal perforation remains a life-threatening condition associated with high mortality. Various factors and operative procedures have been discussed in regard to prediction of outcome, and several scoring systems have been proposed to predict the outcome of critically ill patients. The present study was undertaken to identify factors and determine predictive scoring systems for the postoperative outcome of patients with colorectal perforation. METHODOLOGY: Between January 1996 and December 2000, 45 consecutive patients underwent emergency operation for colorectal perforation. Twelve patients (26.7%) died in hospital. The correlation of outcome with various preoperative factors, APACHE II and SOFA scores were assessed retrospectively. RESULTS: Univariate analysis showed that outcome was significantly related to maximum SOFA score (p=0.0069). Multivariate logistic regression analysis demonstrated that the maximum SOFA score was an independent predictor (p=0.016). Serum creatinine level (p=0.013) and platelet count (p=0.036) were associated with patient outcome in the SOFA score. Patients with a SOFA score higher than 7 had a greater risk of hospital death (p=0.0085). CONCLUSIONS: The maximum postoperative SOFA score is a useful predictor of the outcome from surgery for colorectal perforation.

Effect of ketoconazole on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor teneligliptin: an open-label study in healthy white subjects in Germany.

OBJECTIVE: The aim of this study was to examine the effect of ketoconazole, a potent cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) inhibitor, on teneligliptin pharmacokinetics and to evaluate the safety of combined administration of teneligliptin with ketoconazole. METHODS: This open-label, fixed-sequence study was conducted in 16 healthy adult volunteers in Germany. On day 1, under fasting conditions, 20 mg of teneligliptin was administered to evaluate the pharmacokinetics of teneligliptin alone. For 3 days (days 8-10), 400 mg of ketoconazole was administered once daily. On day 11, teneligliptin 20 mg and ketoconazole 400 mg were concurrently administered, and for 2 days (days 12 and 13), ketoconazole was administered once daily. The pharmacokinetic parameters (Cmax, Tmax, AUC, terminal t½, apparent total plasma clearance, and Vd during the terminal phase) of teneligliptin on days 1 and 11 were calculated. The safety profile was evaluated based on adverse events and clinical findings. To investigate the role of human P-gp in membrane permeation of teneligliptin, an in vitro study was performed to measure the transcellular transport of teneligliptin across monolayers of human P-gp-expressing cells and control cells. RESULTS: For Cmax and AUC, the geometric least squares mean ratios (90% CIs) of teneligliptin with ketoconazole to teneligliptin alone were 1.37 (1.25-1.50) and 1.49 (1.39-1.60), respectively. There was no change in t½ of the terminal elimination phase. In addition, the tolerability of teneligliptin coadministered with ketoconazole was acceptable. The in vitro study revealed corrected efflux ratios for teneligliptin of 6.81 and 5.27 at teneligliptin concentrations of 1 and 10 µM, respectively. CONCLUSIONS: Because the exposure to teneligliptin in combined administration with ketoconazole, a potent CYP3A4 and P-gp inhibitor, was less than twice that of administration of teneligliptin alone, it is suggested that combined administration of teneligliptin with drugs and foods that inhibit CYP3A4 should not cause a marked increase in exposure. The results of our in vitro study suggest that teneligliptin is a substrate of P-gp. CLINICAL TRIAL REGISTRATION: EudraCT No. 2009-016652-51.

Favorable effect on postgraduate clinical practice of a drug-interaction exercise for undergraduate students.

AIM: Undergraduate students in Jichi Medical School participated in a laboratory exercise investigating the furosemide-probenecid interaction at the end of their clinical pharmacology (CP) course. The aim of this study was to determine whether they learned to recognize drug interactions better than students who did not take such a course. METHODS: We conducted a postal survey of physicians who had graduated from Jichi Medical School or from other medical schools without a CP course including the exercise. Questions were asked concerning: (1) the recognition of furosemide-probenecid and nine other drug interactions, and (2) the need to anticipate drug interactions and their adverse effects before writing prescriptions. RESULTS: The degree of the recognition of all drug interactions, and the percentage of physicians who responded that knowledge of drug interactions and adverse effects were essential before writing prescriptions, were significantly greater in physicians who had taken an undergraduate CP course than in those who had not. CONCLUSIONS: CP courses with specific laboratory exercises on drug interactions lead future physicians to recognize drug interactions and their adverse effects.

Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam.

OBJECTIVE: Grapefruit juice (GFJ) inhibits cytochrome P450 (CYP) 3A4 in the gut wall and increases blood concentrations of CYP3A4 substrates by the enhancement of oral bioavailability. The effects of GFJ on two benzodiazepine hypnotics, triazolam (metabolized by CYP3A4) and quazepam (metabolized by CYP3A4 and CYP2C9), were determined in this study. METHODS: The study consisted of four separate trials in which nine healthy subjects were administered 0.25 mg triazolam or 15 mg quazepam, with or without GFJ. Each trial was performed using an open, randomized, cross-over design with an interval of more than 2 weeks between trials. Blood samples were obtained during the 24-h period immediately following the administration of each dose. Pharmacodynamic effects were determined by the digit symbol substitution test (DSST) and utilizing a visual analog scale. RESULTS: GFJ increased the plasma concentrations of both triazolam and quazepam and of the active metabolite of quazepam, 2-oxoquazepam. The area under the curve (AUC)(0-24) of triazolam significantly increased by 96% (p<0.05). The AUC(0-24) of quazepam (+38%) and 2-oxoquazepam (+28%) also increased; however, these increases were not significantly different from those of triazolam. GFJ deteriorated the performance of the subjects in the DSST after the triazolam dose (-11 digits at 2 h after the dose, p<0.05), but not after the quazepam dose. Triazolam and quazepam produced similar sedative-like effects, none of which were enhanced by GFJ. CONCLUSION: These results suggest that the effects of GFJ on the pharmacodynamics of triazolam are greater than those on quazepam. These GFJ-related different effects are partly explained by the fact that triazolam is presystemically metabolized by CYP3A4, while quazepam is presystemically metabolized by CYP3A4 and CYP2C9.

Inhibition of Rho-kinase reduces renal Na-H exchanger activity and causes natriuresis in rat.

Rho-kinase regulates the actin cytoskeleton and therefore modulates transport. The role of Rho-kinase in Na-H exchanger (NHE) activity of rat proximal convoluted tubules (PCTs) was investigated using (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632), a specific inhibitor of Rho-kinase. In spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats, apical and basolateral NHE activities were determined by measuring cell pH recovery following luminal NH4+ prepulse and basolateral sodium removal, respectively. Apical NHE activity was greater in 8 to 9 week old hypertensive SHR compared with WKY. Although Y-27632 suppressed pH(i) recovery in both strains, sensitivity was 50-fold higher in adult SHR. Y-27632 suppressed basolateral NHE in both strains with similar sensitivity. Apical NHE activity was not greater in 5-week-old, not yet hypertensive, SHR rats compared with WKY. In clearance studies, Na excretion was less in SHR than in WKY rats. Y-27632 increased Na excretion and fractional excretion Na in both strains but more so in SHR. (22)Na uptake of the brush border membrane vesicle taken from Y-27632-treated rats decreased more than that from vehicle-treated animals in both adult SHR and WKY. We conclude that apical NHE activity is increased in SHR PCT compared with controls and that inhibition of Rho-kinase reduces PCT NHE activities and causes natriuresis.