title: Sites of biotransformation for the cyclosporin derivative SDZ IMM 125 using human liver and kidney slices and intestine. Comparison with rat liver slices and cyclosporin A metabolism.
abstract: 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 biotransformation is less than for CSA. Initial rates of IMM metabolite formation in the human liver slice cultures are 6.6 +/- 2.8 nmol/hr/g liver at 1 microM IMM and 24.3 +/- 22.9 nmol/hr/g liver at 10 microM IMM, whereas the rate of CSA metabolite formation is 1.8-fold faster at both concentrations. The percentage of unchanged IMM is 73% at 1 microM and 80% at 10 microM after 24 hr, reflecting the lower extent of IMM metabolism, about one-third (1 microM) and one-half (10 microM) that of CSA. In rat liver slices, IMM is metabolized to the same primary metabolites as in human liver slices, but more slowly and remains 90% unchanged at 24 hr. Human jejunum formed the same primary metabolites of IMM and CSA as in liver. Upscaling the slice rate of biotransformation revealed that human jejunum would contribute considerably to the first-pass of IMM and CSA, being approximately 2 to 3-fold slower than the rate in liver. The inhibition of both IMM and CSA biotransformation by triacetyloleandomycin implicates the involvement of cytochrome P4503A proteins. Human kidney cortex slices metabolized IMM to IMM1 and IMM9, accounting for approximately 75% of the total metabolites. Total metabolite formation represented approximately 64% of liver metabolite formation.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Sandoz Pharma Ltd., Basel, Switzerland.
authors.forename: A E
authors.initials: AE
authors.lastname: Vickers
authors.forename: R L
authors.initials: RL
authors.lastname: Fisher
authors.forename: K
authors.initials: K
authors.lastname: Brendel
authors.forename: J
authors.initials: J
authors.lastname: Guertler
authors.forename: R
authors.initials: R
authors.lastname: Dannecker
authors.forename: B
authors.initials: B
authors.lastname: Keller
authors.forename: V
authors.initials: V
authors.lastname: Fischer
mesh_terms: D000818:Animals; D001665:Binding Sites; D001711:Biotransformation; D016572:Cyclosporine / Q000378:metabolism*; D003524:Cyclosporins / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003524:Cyclosporins; D016572:Cyclosporine; C075935:SDZ IMM 125