The pharmacokinetics, efficacy and safety of glimepiride were investigated in a single- and a multiple-dose open study in patients with non-insulin-dependent diabetes mellitus and renal impairment and an initial creatinine clearance above 10 ml/ min. Patients were divided into three groups with creatinine clearance above 50 ml/min, 20-50 ml/min and under 20 ml/min. Fifteen fasting patients received a single dose of 3 mg glimepiride and serial blood and urine samples were taken over 24 h for pharmacokinetic and efficacy analyses. A further 16 patients received glimepiride over a 3-month period, an initial dose of 1 mg glimepiride being adjusted within the range 1 to 8 mg to achieve good glucose control. Pharmacokinetic evaluation was done on day 1 and after 3 months. Mean relative total clearance and mean volume of distribution of both single (41.6 ml/ min and 8.47 litres, respectively, when creatinine clearance was above 50 ml/min) and multiple doses of glimepiride increased in proportion to the degree of renal impairment (to 91.1 ml/min and 14.98 litres, respectively, when creatinine clearance was below 20 ml/min, single dose), whereas the terminal halflife and mean time remained unchanged. Lower relative total clearance and renal clearance of both glimepiride metabolites correlated significantly with lower creatinine clearance values. Of the 16 patients 12 required between 1 and 4 mg glimepiride to stabilize their fasting blood glucose. Glimepiride was well-tolerated and there were no drug-related adverse events. In conclusion glimepiride is safe, effective and has clearly-definable pharmacokinetics in diabetic patients with renal impairment. The increased plasma elimination of glimepiride with decreasing kidney function is explainable on the basis of altered protein binding with an increase in unbound drug.

Bei gesunden Erwachsenen wurden Serum-und Harnspiegelbestimmungen nach intravenöser Injektion und Dauerinfusion von Cefazolin im Vergleich zu Cefalotin und Cefradin durchgeführt und die Antibiotikakonzentrationen in künstlich erzeugten Hautbiasen gemessen. Nach intravenöser Injektion von 1 g Cefazolin betrugen die mittleren Serumspiegel nach einer Stunde 52,1 .tg/ml, nach 2 Stunden 33,0 .tg/ml und nach 6 Stunden 5,6 ig/ml (bei Cefalotin nur 2,9, 0,6 und < 0,1 pg/ml). Bei intravenöser Dauerinfusion (0,166 g/h = 4 g in 24 h) war der Blutspiegel Totalclearance (mI/mm)

Twelve healthy fasting male volunteers received glimepiride in 1, 2, 4 or 8 mg single oral doses. On the days when glimepiride was taken, the subjects were given a standardised carbohydrate diet (18 bread exchange units) and drank 125 ml of water hourly. Blood and urine samples were taken before drug administration and afterwards for up to 36 hours (blood) and 48 hours (urine) to determine serum and urinary concentrations of glimepiride and its hydroxy- and carboxy-metabolites (M1 and M2). The areas under the curve for glimepiride after oral doses of 1 to 8 mg and the urinary recovery of its metabolites M1 and M2 were dose linear. All confidence intervals were well contained within the bioequivalence range of 80-125%. There was a statistically significant difference for Cmax values of glimepiride between doses after dose normalisation. A dose-dependent increase for Cmax was nevertheless clearly observed with a correlation coefficient of r=0.90. The pharmacokinetics of glimepiride are dose linear in the dose range 1 to 8 mg, and glimepiride was safe and well tolerated in healthy volunteers.

Twelve healthy fasting male volunteers received a single 1.0 mg dose of glimepiride either as an intravenous injection over one minute or as a tablet. Blood and urine samples were taken before drug administration and afterwards for up to 24 hours (blood) and 48 hours (urine) to determine serum and urinary concentrations of glimepiride and its hydroxy- and carboxy-metabolites (M1 and M2). There were no statistically significant differences between mean serum pharmacokinetic parameters for the oral and intravenous formulations either with glimepiride or M1. Mean urinary recovery of M1 plus M2 was 50% of the dose for the glimepiride tablet and 51% for the intravenous injection. The absolute bioavailability of the tablet formulation was 107% (AUDC(glimepiride)), 109% (AUDC(M1)) and 97% (urinary recovery). The tablet formulation of glimepiride is completely bioavailable and was safe and well tolerated in healthy volunteers.

Grötsch, Hropot, Klaus, Malerczyk and Mattenheimer: Enzymuria of the rat: Biorhythms and sex differences 343 Summary: Alanine aminopeptidase, -glutamyltransferase and N-acetyl-ß-Z)-glucosaminidase were measured daily over 65 days in 24-hour urine of male and female Wistar rats. The mathematical evaluation was based on the Föw/er-analysis. The excretion of alanine aminopeptidase and -glutamyltransferase was higher in male than in female rats. This sex-dependent difference was not observed for N-acetyl-ß-/)-glucosaminidase. The excretion of the 3 enzymes followed a biorhythm with a dominant period of 7 days forglutamyltransferase and N-acetyl-ß-£>-glucosaminidase and one of 9 days for alanine aminopeptidase. Biorhythms and sex differences of enzymuria should be considered in experimental designs. Enzymurie der Ratte: Biorhythmen und GeschlechtsdifferenzenZusammenfassung: Alaninaminopeptidase, -Glutamyltransferase und N-Acetyl-ß-D-glucosaminidase wurden täglich über 65 Tage bei männlichen und weiblichen Wistar-Ratten im 24 h-Urin gemessen. Die Ergebnisse wurden vermittels fbwr/er-Anälyse ausgewertet. Die Ausscheidung von Alaninaminopeptidase und -Glutamyltransferase zeigte deutliche geschlechtsabhängige Unterschiede, wobei von männlichen Ratten mehr ausgeschieden wurde als von weiblichen Tieren. N-Acetyl-ß-/)-glucosaminidase zeigt diese Unterschiede nicht. Die Ausscheidung der drei Enzyme unterlag Biorhythmen mit Periodenlängen von sieben Tagen für -Glutamyltransferase und N-Acetyl-ß-jp-glucosaminidase und neun Tagen für Alaninaminopeptidase. Biorhythmen und Geschlecht$differenzen in der Enzymurie sind bei Versuchsplanungen zu berücksichtigen. Introduction. , « , , years the rat has been used äs the main experimental Urine enzymes äre being used with increasing animal in enzyine excretion studies. This animal frequency äs sensitive indicatöfs for early detection shows significant enzymuria when substances are of renal damage. Many investigatiöns include a administered which cause increased enzymuria in discussipn of biörhythms in man and animals, re-man. The rat tolerates well single-cage housing in speetively (l -3), A few reports on experimental ani-long term experiments. Enzymes with the smallest mal models document this coherence of biörhythms experimental Variation and good reproducibility are and nephrptoxicity with a close correlation between alanine aminopeptidase, -glutamyltransferase and enzyme excretion and renal damage. Of the large N-acetyl-ß^jD-glucosaminidase. The aim of this study nuinber of urine enzymes, it is mainly those from the was to apply modern mathematical methods to the proximal tübular cells that are of particular interest investigation of biörhythms and sex-specific for toxicological and clinical investigatiöns. In recent differences in the excretion of these enzymes over a