Abstract
The metabolism of retigabine in humans and dogs is dominated byN-glucuronidation (McNeilly et al., 1997), whereas in rats, a multitude of metabolites of this new anticonvulsant is observed (Hempel et al., 1999). The comparison of the in vivo and in vitro kinetics of retigabine N-glucuronidation in these species identified a constant ratio between retigabine and retigabineN-glucuronide in vivo in humans and dog. An enterohepatic circulation of retigabine in these species is likely to be the result of reversible glucuronidation-deglucuronidation reactions. Rats did not show such a phenomenon, indicating that enterohepatic circulation of retigabine via retigabineN-glucuronide does not occur in this species. In the rat, 90% of retigabine N-glucuronidation is catalyzed by UDP-glucuronosyltransferase (UGT)1A1 and UGT1A2, whereas family 2 UGT enzymes contribute also. Of ten recombinant human UGTs, only UGTs 1A1, 1A3, 1A4, and 1A9 catalyzed theN-glucuronidation of retigabine. From the known substrate specificities of UGT1A4 toward lamotrigine and bilirubin and our activity and inhibition data, we conclude that UGT1A4 is a major retigabine N-glucuronosyl transferase in vivo and significantly contributes to the enterohepatic cycling of the drug.
Footnotes
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Send reprint requests to: Dr. Thomas Kronbach, Corporate Research & Development ASTA Medica Group, Biochemistry Dresden, Arzneimittelwerk Dresden GmbH, Meiβner Str. 191, D-01445 Radebeul, Germany. E-mail: Dr_Thomas.Kronbach{at}astamedica.de
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This work was supported in part by grants from the Sächsisches Ministerium für Arbeit und Wirtschaft (project number 1791) and by United States Public Health Service Grant GM49135 (R.H.T).
- Abbreviations used are::
- UGT
- UDP-glucuronosyltransferase
- AUC
- area under the plasma concentration-time curve from t0 up to t∞
- HPLC
- high-performance liquid chromatography
- EHC
- enterohepatic circulation
- UDPGA
- UDP-glucuronic acid
- Received July 22, 1998.
- Accepted January 25, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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