Absorption and disposition of SDZ IMM 125, a new cyclosporine derivative, in rats after single and repeated administration

A Bruelisauer, R Kawai, P Misslin and M Lemaire

Sandoz Pharma Ltd., Basel, Switzerland.

The absorption and disposition of SDZ IMM 125, a new derivative of the cyclosporine family, were studied in rats after oral, subcutaneous, or intravenous dosing. The absolute bioavailability of 53% observed after a single oral dose of 10 mg/kg was variable and similar to that observed with cyclosporine A. The bioavailability was not modified during 21 days of daily treatment. The fraction of SDZ IMM 125 bound to plasma proteins was moderate (70% vs. 95% for cyclosporine A), whereas the uptake by blood cells was considerably higher than that of cyclosporine A varying from 80% at 50 ng/ml to 30% at 10,000 ng/ml. SDZ IMM 125 distributes extensively in most tissues except in brain; multiple oral administration does not modify the tissue distribution and indicates that there is no drug accumulation. The tissue distribution of SDZ IMM 125 is lower than that of cyclosporine A; the volume of distribution of this drug (2.6 liters/kg) is roughly half that of cyclosporine A, which is consistent with the lower lipophilicity of this compound. The systemic clearance of SDZ IMM 125 is relatively low (1.3 ml/min) and comparable to that of cyclosporine A. The excretion of SDZ IMM 125 occurs essentially through the liver via the bile; biliary and urinary excretion of unchanged drug represents 18% and 7% of the dose, respectively. The significant excretion of unchanged drug in both bile and urine represents a major difference compared with cyclosporine A, which is not excreted as unchanged drug to any extent.

Volume 22, Issue 2, pp. 194-199, 03/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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