HYDROXYETHYL CYCLOSPORINE-A INDUCES AND DECREASES P4503A AND P-GLYCOPROTEIN LEVELS IN RAT-LIVER

1. A new immunosuppressant SDZ IMM 125 (IMM), the hydroxyethyl derivat ive of D-serine(8)-cyclosporin (clyclosporin A, CSA), induced or decre ased the liver P450s of rat, in particular the 3A proteins, depending on the dose and duration of exposure. Doses of 20 mg/kg/day for 2 week s and 10 mg/kg/day for 26 weeks induced the rat liver 3A levels 2- and 1.8-fold respectively, whereas 52 weeks of 24 mg/kg/day decreased rat 3A levels by 22%. High doses of IMM, 100 mg/kg/day for 26 weeks, sign ificantly decreased the 3A levels by 56%. 2. Changes in the rare of IM M biotransformation paralleled the changes in the levels of liver 3A i ndicating that liver 3A levels could influence the clearance of IMM. 3 . Both IMM and CSA affected liver and kidney P-glycoprotein (Pgp) leve ls. The increases measured after short-term treatment (20 mg/kg/day fo r 2 weeks) in the liver(1.8-fold) and kidney (13-fold) were less prono unced in the long-term studies in which liver Pgp levels w ere increas ed 1.4-fold (48 mg/kg/day for 52 weeks). At higher doses (100 mg/kg/da y for 26 weeks) Pgp levels were significantly decreased. The modulatio n of Pgp levels by IMM did not parallel the changes in 3A levels, indi cating that Pgp regulation is most likely due to a direct effect of th e cyclosporin rather than a co-regulation mechanism linked to 36 or P4 501A modulation. 4. Increased arachidonic metabolism to the 19- and 20 -HETE metabolites, a possible mechanism of thr cyclosporin-induced ren al hypertension, occurred in the liver microsomes and not the kidney S 9 fraction of the 2-week study, and only at very high doses (100 mg/kg /day) in the longer studies (26 weeks).