Hydroxyethyl cyclosporin A induces and decreases P4503A and P-glycoprotein levels in rat liver

Xenobiotica. 1996 Jan;26(1):27-39. doi: 10.3109/00498259609046686.


1. A new immunosuppressant SDZ IMM 125 (IMM), the hydroxyethyl derivative of D-serine8-cyclosporin (cyclosporin A, CSA), induced or decreased 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 weeks 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 the 3A levels by 22%. High doses of IMM, 100 mg/kg/day for 26 weeks, significantly decreased the 3A levels by 56%. 2. Changes in the rate of IMM biotransformation paralleled the changes in the levels of liver 3A indicating that liver 3A levels could influence the clearance of IMM. 3. Both IMM and CSA affected liver and kidney P-glycoprotein (Pgp) levels. The increases measured after short-term treatment (20 mg/kg/day for 2 weeks) in the liver (1.8-fold) and kidney (1.3-fold) were less pronounced in the long-term studies in which liver Pgp levels were increased 1.4-fold (48 mg/kg/day for 52 weeks). At higher doses (100 mg/kg/day for 26 weeks) Pgp levels were significantly decreased. The modulation of Pgp levels by IMM did not parallel the changes in 3A levels, indicating that Pgp regulation is most likely due to a direct effect of the cyclosporin rather than a co-regulation mechanism linked to 3A or P4501A modulation. 4. Increased arachidonic metabolism to the 19- and 20-HETE metabolites, a possible mechanism of the cyclosporin-induced renal hypertension, occurred in the liver microsomes and not the kidney S9 fraction of the 2-week study, and only at very high doses (100 mg/kg/day) in the longer studies (26 weeks).

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Arachidonic Acid / metabolism
  • Biotransformation
  • Cyclosporins / pharmacokinetics
  • Cyclosporins / pharmacology*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / metabolism*
  • Enzyme Induction / drug effects
  • Immunoblotting
  • Immunosuppressive Agents / pharmacokinetics
  • Immunosuppressive Agents / pharmacology*
  • In Vitro Techniques
  • Kidney / drug effects
  • Kidney / enzymology
  • Kidney / metabolism
  • Lauric Acids / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Mixed Function Oxygenases / biosynthesis
  • Mixed Function Oxygenases / metabolism*
  • Oxidation-Reduction
  • Rats
  • Rats, Wistar
  • Subcellular Fractions / metabolism


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cyclosporins
  • Immunosuppressive Agents
  • Lauric Acids
  • lauric acid
  • Arachidonic Acid
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • SDZ IMM 125