Pharmacokinetics of the enantiomers of thalidomide

Sammanfattning: Thalidomide has a chiral center and the racemate of (+)-(R) and (-)-(S)-thalidomide was introduced as a hypnotic/sedative drug in 1957. In 1961 it was withdrawn due to teratogenicity and neuropathy. There is a growing interest in thalidomide treatment of immunomodulatory diseases. Given this renewed interest the aim of this thesis was to achieve a more rational use of thalidomide. Therefore some chemical and pharmacological aspects of the racemate and of the enantiomers were studied, with special emphasis on the pharmacokinetics of the enantiomers. HPLC assays for determination of thalidomide, its enantiomers and some hydroxylated metabolites were developed. So were different compartment models to describe the pharmacokinetics of the enantiomers of oral and i.v. administration. Solutions for i.v. administration of the enantiomers and methodology for concentration-effect relationship studies (sedation) of the enantiomers were developed. In addition, methods were created to avoid hydrolysis and chiral inversion in blood samples and during assay. The plasma protein binding was 56 for (+)-(R)- and 66% for (-)-(S)-thalidomide. Serum albumin catalysed the inversion, but not the degradation, at pH 7.4. This catalysis was inhibited to various extents in human plasma, and by capric acid, ASA or physostigmine. This supports that chiral inversion and hydrolysis occur by different mechanisms. The pharmacokinetics in a total of 22 healthy male volunteers was studied. The t½ was lower (4.7 h) than previously reported. CLtot was 14 and 24 L/h, and Vdss was 48 and 66 L for (+)-(R)- and (-)-(S)-thalidomide, respectively. It was shown that (+)-(R)-thalidomide is responsible for the sedative effects in humans. Other researchers have shown that the teratogenic and immunomodulatory effects possibly reside in the (-)-(S)-enantiomer. However, the tragedy in the 60s could not have been avoided with the use of the (+)-(R)-enantiomer since this study shows that there is rapid chiral inversion between the enantiomers in humans. The (+)-(R)-enantiomer is predominating at pseudoequilibrium, 8-10 hours after an oral dose of the separate enantiomers. 5'-hydroxy thalidomide but not three other hydroxylated metabolites were found in low concentrations in plasma from all 8 subjects, with a detection limit of 1-2 ng/ml. Three of the hydroxylated metabolites were identified after incubation with human S9 liver homogenate. Further development and studies of oral and i.v. administration forms based on (-)-(S)-thalidomide is suggested.