Species-dependent hepatic metabolism of immunosuppressive agent tacrolimus (FK-506).
The current study aims to investigate species-related differences in the in-vitro hepatic metabolism of tacroliums using liver microsomes obtained from rat, hamster, guinea pig, rabbit, pig, dog, baboon and humans. Tacrolimus metabolism was characterized using high-performance liquid chromatography- ultraviolet light (HPLC-UV) and two soft ionization mass spectrometric techniques; matrix-assisted lasers desorption/ionization (MALDI) and time-of-flight-secondary ion mass spectrometry (TOF-SIMS). The extent of tacrolimus metabolism, when normalized to the cytochrome P-450 content, was in the order: rat < hamster < rabbit < pig < guinea pig < dog < human < baboon. Tacrolimus metabolism exhibited significant qualitative and quantitative differences between the animal species tested. Desmethyl- (MI-MIII), didesmethyl- (MIV-MVI), monohydroxy- (MVII), dihydroxy- (MVIII), epoxide- (MIX), dihydrodiol- (MX), monodesmethyl and monohydroxy- (MXI-MXIII), and didesmethyl and monohydroxy- (MXIV-MXVI) tacroliums metabolites were identified in the species tested. MI-MX were identified in all the species tested; MXI-MXVI were identified in all species except rat, rabbit and guinea pig; and MXIV-MXVI were identified only in baboon. The current investigation was unable to detect any phase II metabolites due to the limitations of the test system used. The analytical methods were not able to differentiate optical and positional isomers of metabolites due to the nature of the analytical tools used, therefore groups of metabolites were identified based on their molecular weights and available information. From the current in-vitro metabolism studies, the pattern of tacroliums metabolism in baboons closely resembled that in humans and thus it is ideal for studying tacroliums metabolism-related work of clinical relevance.
Tata
P N V
PN
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA. drprasadtata@yahoo.com
Subbotina
N
N
Burckart
G J
GJ
Muddiman
D C
DC
Gusev
A I
AI
Hercules
D M
DM
Starzl
T E
TE
Venkataramanan
R
R
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D010215:Papio; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016559:Tacrolimus / Q000737:chemistry / Q000378:metabolism*
D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; D016559:Tacrolimus