Coincubation of tissue slices, a new way to study metabolic cooperation between organs: hepatorenal cooperation in the biotransformation of CGP 47 969 A.
BACKGROUND
There is limited information on in vitro/ex vivo tools to be used for studying interorgan metabolic cooperation. We report here the use of the tissue slice technique for this purpose.


METHODS
Rat liver and kidney slices were used to study metabolic cooperation for the metabolism of CGP 47 969, a potential anti-inflammatory compound which in vivo is extensively conjugated with glutathione and subsequently degraded via the mercapturic acid pathway.


RESULTS
Upon incubation with liver slices, CGP 47 969 was extensively conjugated with GSH whilst degradation of the GSH conjugate was moderate. Upon incubation with kidney slices, conjugation of CGP 47 969 with GSH was moderate but degradation of the GSH conjugate was complete. Upon coincubation of CGP 47 969 with liver and kidney slices, both conjugation with GSH and its subsequent degradation were almost complete. Thus, coincubation of liver and kidney slices permitted the efficient in vitro reproduction of the complete biotransformation of CGP 47 969 via its GSH conjugate to the ultimate mercapturic acid metabolite in a one step procedure.


CONCLUSIONS
This novel slice coincubation culture could serve as an in vitro model for interorgan cooperation in multistep metabolic processing.
Kretz
O
O
Novartis Pharma, PCS-Europe ADME, WKL-135.4.24, CH-4002 Basel, Switzerland. olivier.kretz@pharma.novartis.com
Guenat
C
C
Beilstein
P
P
Gross
G
G
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D018920:Coculture Techniques / Q000379:methods; D003470:Culture Media; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009924:Organ Culture Techniques / Q000379:methods; D010879:Piperazines / Q000378:metabolism*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization
C092257:CGP 47969A; D003470:Culture Media; D010879:Piperazines; D005978:Glutathione; D000111:Acetylcysteine