SITES OF BIOTRANSFORMATION FOR THE CYCLOSPORINE DERIVATIVE SDZ IMM-125 USING HUMAN LIVER AND KIDNEY SLICES AND INTESTINE - COMPARISON WITH RAT-LIVER SLICES AND CYCLOSPORINE-A METABOLISM

SDZ IMM 125 (IMM), the hydroxyethyl derivative of cyclosporin A (CSA), is metabolized by human liver slices to analogous primary metabolites , hydroxylated IMM1 and IMM9 and N-demethylated IMM4N, as for CSA (M17 /AM1, M1/AM9, and M21/AM4N), but the rate and extent of IMM biotransfo rmation is less than for CSA. Initial rates of IMM metabolite formatio n in the human liver slice cultures are 6.6 +/- 2.8 nmol/hr/g liver at 1 mu M IMM and 24.3 +/- 22.9 nmol/hr/g liver at 10 mu M IMM, whereas the rate of CSA metabolite formation is 1.8-fold faster at both concen trations. The percentage of unchanged IMM is 73% at 1 mu M and 80% at 10 mu M after 24 hr, reflecting the lower extent of IMM metabolism, ab out one-third (1 mu M) and one-half (10 mu M) that of CSA, In rat live r slices, IMM is metabolized to the same primary metabolites as in hum an liver slices, but more slowly and remains 90% unchanged at 24 hr. H uman jejunum formed the same primary metabolites of IMM and CSA as in liver. Upscaling the slice rate of biotransformation revealed that hum an jejunum would contribute considerably to the first-pass of IMM and CSA, being similar to 2- to 3-fold slower than the rate in liver. The inhibition of both IMM and CSA biotransformation by triacetyloleandomy cin implicates the involvement of cytochrome P4503A proteins. Human ki dney cortex slices metabolized IMM to IMM1 and IMM9, accounting for si milar to 75% of the total metabolites. Total metabolite formation repr esented similar to 64% of liver metabolite formation. In conclusion, I MM is metabolized at several sites (human liver, jejunum, and kidney), contributing to the variation in cyclosporin blood levels in humans.