Pharmacokinetics of linsidomine (SIN 1) after single and multiple intravenous short infusions in patients with renal insufficiency

Pharmacokinetic measurements were performed in two groups of patients with coronary heart disease (CHD) after single and multiple dosing of 2 mg linsidomine (SIN 1). The drug was administered by intravenous short time infusion in 12 CHD-patients with renal insufficiency (RI group, Clcr: 11 +/- 6 ml/min) and in 12 CHD-patients with normal kidney function (control group, Clcr: 88 +/- 22 ml/min). The measurement of plasma concentration time courses of total SIN 1C (SIN 1 + SIN 1C) was found to be suitable for an estimation of the SIN 1C related half-life of the terminal phase (t50% = 1.5 +/- 0.5 h), as SIN 1 was eliminated from plasma rapidly (t50% = 12 to 20 min). Furthermore, the mean total SIN 1C plasma profiles were equal after single and multiple administration of the drug giving evidence that SIN 1C is not accumulating during repetitive dosing of SIN 1 in patients with renal disease. The mean maximum renal fraction of total SIN 1C excretion of RI-subjects (fe = 0.8 +/- 0.8% of dose) was significantly different from the corresponding mean value of the control group (fe(N) = 5.8 +/- 5.1% of dose). No differences were found for fe and fe(N) between day 1 and day 4. As SIN 1 is degraded in plasma very rapidly and as SIN 1C is cleared mainly extrarenally, any restrictions concerning repetitive SIN 1 dosage regimen should not be considered for CHD-patients with renal failure.