The uricosuric effect of DuP-753, a novel, specific angiotensin II receptor antagonist, has been explored in a healthy male Japanese volunteers, given single oral doses of 25, 50, 100 or 200 mg (n = 6), or 100 mg (n = 6) or placebo (n = 3) once daily for 7 consecutive days. In the single-dose study, serum uric acid measured at 4 h after dosing showed a dose dependent decrease; the reductions from the corresponding pre-dose values were: 0.32 (25 mg), 0.77 (50 mg), 1.25 (100 mg) and 1.33 mg.dl-1 (200 mg). The urinary excretion of uric acid within the first 4 h after treatment was also increased in a dose-dependent manner, whereas the urinary excretion of creatinine remained unchanged. In the multiple-dose study, DuP-753 significantly decreased the serum uric acid concentration measured 4 h both after the first (pre-dose value: 5.68 vs 4 h after: 4.48 mg.dl-1) and last administrations (4.42 mg.dl-1). Simultaneously, the ratio of urinary uric acid to creatinine excretion was significantly increased within the first 4 h both after the first (DuP-753: 1.190 vs placebo: 0.576) and last administrations (1.02 vs 0.576). The findings suggest that DuP-753 possesses a uricosuric effect both after single and multiple doses in healthy subjects. The effect should be further examined in hypertensive patients.

The safety and pharmacokinetics of a novel recombinant soluble human thrombomodulin, ART-123 were evaluated in single- and multiple-dose studies involving 16 healthy male volunteers. ART-123 was administered by intravenous infusion over 2 hours. The single-dose study indicated that plasma ART-123 levels at doses of 0.03, 0.1, and 0.3 mg declined biexponentially and those half-lives were approximately 4 hours (t1/2 alpha) and 20 hours (t1/2 beta), respectively. The mean plasma peak concentration and area under the plasma concentration-time curves increased in proportion to the given doses. Mean urinary recovery within the first 48 hours was between 54.3% and 59.8% of dose. In the multiple-dose study, ART-123 was administered at a dose of 0.2 mg once daily for 3 days. ART-123 did not accumulate as judged from plasma concentrations and urinary recovery. There were no abnormal findings in objective symptoms and laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, bleeding time, coagulation and hemostatic parameters, blood chemistry, and urinalysis. There were no significant adverse reactions or abnormalities in physical and laboratory examinations that could definitely be attributed to the drug at a dose of 0.3 mg as a single administration and at a dose of 0.2 mg once daily for 3 days. These results indicate that ART-123 is safe at doses up to 0.2 mg once daily for 3 days and may have clinical application. Further studies are needed, however, to evaluate the safety and pharmacokinetics of ART-123 in the targeted population.

The tolerance and pharmacokinetics of fleroxacin were studied in healthy male adult volunteers. The peak serum concentrations of unchanged fleroxacin were about 1.5, 3 and 5 mg/l at 1-2 h after single oral doses of 100, 200 and 400 mg, respectively. The apparent serum elimination half-life was about 10 h, independent of the dose. Fleroxacin, demethyl fleroxacin and fleroxacin N-oxide excreted in urine over 3 days accounted for about 75%, 5% and 5%, respectively, of the doses. The urine concentrations of unchanged drug were dose-related; the mean concentrations, sustained over 24 h, were about 50, 100 and 150 mg/l after 100, 200 and 400 mg doses, respectively. Food intake did not significantly influence the serum concentration and urinary excretion. Steady state serum concentrations were achieved from day 3 onwards by repeated doses of twice-a-day dosage regimen and were 2-4 and 5-9 mg/l after 200 and 400 mg bid, respectively. The mean concentrations of unchanged drug in urine were about 200 and 300 mg/l at the respective dosages. The pattern of urinary metabolites was not changed by repeated doses and 90% of repeat doses was recovered in urine, including metabolites. The serum protein binding of fleroxacin was 32%. The saliva concentration was 40% of the total serum concentration or 60% of the free serum concentration. The faecal recovery over 3 days was 3% of the dose following a single 200 mg dose after a meal. The unchanged drug concentrations in faeces during 400 mg repeated dosing were 100-150 mg/kg. No severe dose-related side-effects were observed during the study.

Purpose: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme catalyzing the metabolic degradation of the anticancer drug 5-fluorouracil (5-FU). Population studies of DPD activity in peripheral blood mononuclear cells (PBMC) were reported in healthy volunteers and cancer patients. Although these studies were done in mainly Caucasian and African American populations, only a little information is available for a Japanese population. Experimental Design: One hundred fifty healthy Japanese volunteers were screened for a population distribution of PBMC-DPD activity. Genetic analysis of a volunteer with very low DPD activity was carried out by reverse transcriptase-PCR and genomic sequencing. Bacterially expressed recombinant mutant DPD proteins were purified and characterized. Results: Mean and median values of PBMC-DPD activity for 5-FU reduction in the study population were 0.173 and 0.166 nmol/min/mg protein, respectively. A 57-year-old female volunteer (proband in this study) had very low DPD activity (0.014 nmol/min/mg protein) with a very low level of expression of DPD protein. Two novel nucleotide substitutions, at nucleotide positions 1097 (1097G > C) and 2303 (2303C > A), resulting in amino acid substitutions at positions 366 (G366A) and 768 (T768K), respectively, were identified.The G366A mutation caused not only a marked decrease in the affinity of the enzyme to cofactor NADPH but also reducedV max for 5-FUreducing activity to f0.5. T768K mutant lost its activity much faster than did wild DPD. Conclusions: We found one healthy volunteer (0.7% of the population) with very low PBMC-DPD activity due to heterozygosity for a mutant allele of the DPYD gene in a population of 150 Japanese.Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases, uracil and thymine (1), and is also known to be the key enzyme catalyzing the metabolic degradation of the anticancer drug 5-fluorouracil (5-FU; refs. 1, 2). 5-FU has been commonly and widely used as a chemotherapeutic agent for the treatment of cancer of the gastrointestinal tract, breast, and head and neck (3). More than 85% of the given 5-FU is catabolized by DPD (4). The clinical importance of DPD has been shown with the identification of severe or lethal toxicity in patients given 5-FU who are deficient in or have low levels of DPD activity in their peripheral blood mononuclear cells (PBMC; refs. 5 -7).The importance of the role of DPD in 5-FU chemotherapy also has been shown by studies with competitive and irreversible DPD inhibitors (8, 9). Recently, we reported a possible mechanism for the 18 acute deaths of Japanese patients in 1993 that were caused by interactions between oral 5-FU prodrugs and the new oral antiviral drug, sorivudine [1-h-D-arabinofuranosyl-(E )-5-(2-bromovinyl)uracil], which was being used for treatment of herpes zoster (9 -13). Our study indicated that these patients were most likely to have extremely low levels of hepatic DPD activity ...

The pharmacokinetic and pharmacodynamic properties of (+)-sotalol (BMY-5763) were studied to analyse the relationship between plasma concentration and QTc prolongation in healthy male volunteers given single oral doses of 50, 100, 200 and 300 mg, repeated oral doses of 200 mg twice daily for 6.5 days, and single intravenous doses of 1.0 and 1.5 mg kg-1. The plasma concentration of (+)-sotalol peaked about 3 h after oral administration and declined with a half-life of 7.9-9.7 h. The Cmax and AUC showed dose-related increases, while the urinary recovery as the unchanged form remained constant (66-68% of the dose). During repeated oral administration the plasma concentration of (+)-sotalol reached almost a steady state on the 3rd day and there was no change in renal clearance of (+)-sotalol measured on the 1st, 4th and 7th days. After intravenous administration, (+)-sotalol in plasma decreased bi-exponentially with a terminal half-life of 7.6-8.3 h and the urinary recovery as unchanged drug amounted to 84-88% of the dose. The increase in QT interval was significant after a single oral administration except for the lowest dose, and regression analysis revealed a significant correlation between QTc interval and concentration of (+)-sotalol in plasma. The same correlation was evident with repeated oral doses on the 1st, 4th and 7th days. In the case of single intravenous administrations of (+)-sotalol, a combined pharmacokinetic-pharmacodynamic model was attempted by assuming an effect compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

We have studied the pharmacokinetics of tulobuterol given transdermally or by aerosol inhalation in healthy male volunteers. Tulobuterol was rapidly absorbed after inhalation, with a tmax of 0.8-1.5 h. The Cmax and the AUC increased linearly with dose. Tulobuterol was well absorbed after transdermal administration, with an absorption lag-time of about 4 h. The Cmax and AUC increased linearly with dose and the tmax was about 9-12 h. The mean percentage of drug absorbed during the application of a patch for 24 h was 82-90% after a single dose and 82-85% during repeated dosing. The mean urinary recoveries as unchanged drug after a single inhalation and patch application were 3-4% and 5-6% respectively. Tulobuterol did not accumulate during repeated inhalation or transdermal application. It was well tolerated, except for an increase in heart rate of 10-20 beats.min-1 after five repeated applications of a 4 mg patch.

AimsTreatment with vitamin D sterols can lower plasma parathyroid hormone (PTH) in patients with secondary hyperparathyroidism; however, hypercalcaemia, hyperphosphataemia, or both, often develop. Calcimimetic agents, employed in alternative therapeutic approaches, directly inhibit PTH secretion by activating the calciumsensing receptor in the parathyroid glands. MethodsIn this study, patients were given orally 25, 50, and 100 mg doses of the calcimimetic agent KRN 1493 each on two occasions, on the day of haemodialysis and on the day without haemodialysis. ResultsIn the pharmacokinetic results, because the clearance of KR N 1493 by haemodialysis was much smaller than the systemic clearance, the influence of haemodialysis was not remarkable. In the pharmacodynamic study, on both the days with or without haemodialysis, plasma PTH concentrations decreased in a dose-dependent manner. Serum calcium concentrations decreased in association with the decrease in plasma PTH concentrations. Mild dose-dependent adverse effects (mainly nausea) were seen after the administration of KRN 1493 on both the day of haemodialysis and the day without haemodialysis. ConclusionsWe conclude that the pharmacokinetics of KRN 1493 after a single administration were similar on the day of haemodialysis and the day without haemodialysis. KR N 1493 is safe and effective in suppressing PTH secretion and serum calcium concentrations on the day of haemodialysis and on the day without haemodialysis in patients with secondary hyperparathyroidism. Calcimimetic agent KRN 1493 and haemodialysisBr J Clin Pharmacol 57 :6 727

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