RESUMEN
BACKGROUND: The haemodynamic effect of propranolol on portal pressure in patients with portal hypertension is highly variable and does not correlate with propranolol racemate plasma concentrations. AIM: To investigate the stereoselective metabolism of the propranolol enantiomers and its impact on portal haemodynamics in patients with liver cirrhosis since only S-propranolol is haemodynamically active. METHODS: Twenty patients with liver cirrhosis and portal hypertension received 40 mg propranolol orally. Portal blood velocity (PBV) and propranolol stereoisomer plasma concentrations were determined. RESULTS: During the 4 h examination period we observed a significant reduction in PBV (18.3 +/- 2.2%, P < 0.0001) vs. baseline. The area under the curve (AUC) during the study period was significantly different for the two isomers (S-propranolol 1217.0 +/- 118.5 nmol.h/L; R-propranolol 728.8 +/- 103.8 nmol.h/L, P < 0.0001). Seven patients (35%) were portal haemodynamic non-responders to propranolol. Propranolol stereoisomer AUC values were no different between responders (S-propranolol 1133. 3 +/- 132.0 nmol.h/L; R-propranolol 718.0 +/- 129.7 nmol.h/L) and non-responders (S-propranolol 1371.8 +/- 250.5 nmol.h/L; R-propranolol 746.9 +/- 200.3 nmol.h/L); neither was there a correlation between propranolol enantiomer plasma concentrations and the portal haemodynamic effect. CONCLUSIONS: Our data demonstrate a stereoselective metabolism of propranolol enantiomers in liver cirrhosis. However, following oral propranolol administration, stereoisomer plasma concentrations do not predict the portal haemodynamic effect.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Antihipertensivos/uso terapéutico , Hemodinámica/efectos de los fármacos , Hipertensión Portal/tratamiento farmacológico , Circulación Hepática/efectos de los fármacos , Cirrosis Hepática/tratamiento farmacológico , Propranolol/uso terapéutico , Antagonistas Adrenérgicos beta/sangre , Antagonistas Adrenérgicos beta/farmacocinética , Antihipertensivos/sangre , Antihipertensivos/farmacocinética , Área Bajo la Curva , Femenino , Humanos , Hipertensión Portal/fisiopatología , Cirrosis Hepática/fisiopatología , Masculino , Persona de Mediana Edad , Propranolol/sangre , Propranolol/farmacocinética , EstereoisomerismoRESUMEN
Tramadol, racemic 1-(3-methoxyphenyl)-2-(dimethylaminomethyl)cyclohexane-1-ol, is an effective analgesic drug. Metabolites of tramadol described so far originate from O- and N-demethylation and are excreted in urine directly or after conjugation. A further metabolite was found in human liver microsome incubations and in the urine of volunteers after ingestion of tramadol. To elucidate the structure of the new metabolite, seven deuterated isotopomers of tramadol have been synthesized and ingested by volunteers. The mass spectra of the metabolites derived showed (i) that it was a hydroxy metabolite, (ii) that the hydroxy group was not located on the aromatic ring, the side chain, or the positions 2 and 6 of the cyclohexane ring, (iii) that the hydroxy-group was introduced to one of the the positions 3, 4 or 5 of the cyclohexane ring. The hydroxy metabolite was formed preferentially from the (-)-enantiomer, (1S,2S)-tramadol.
Asunto(s)
Analgésicos Opioides/metabolismo , Tramadol/metabolismo , Analgésicos Opioides/química , Analgésicos Opioides/orina , Deuterio , Cromatografía de Gases y Espectrometría de Masas , Humanos , Hidroxilación , Masculino , Estructura Molecular , Estereoisomerismo , Tramadol/química , Tramadol/orinaRESUMEN
Abstract Tramadol, racemic 1-(3-methoxyphenyl)-2-(dimethylaminomethyl)cyclohexane-1-ol, is an effective analgesic drug. Metabolites of tramadol described so far originate from O- and N-demethylation and are excreted in urine directly or after conjugation. A further metabolite was found in human liver microsome incubations and in the urine of volunteers after ingestion of tramadol. To elucidate the structure of the new metabolite, seven deuterated isotopomers of tramadol have been synthesized and ingested by volunteers. The mass spectra of the metabolites derived showed (i) that it was a hydroxy metabolite, (ii) that the hydroxy group was not located on the aromatic ring, the side chain, or the positions 2 and 6 of the cyclohexane ring, (iii) that the hydroxy-group was introduced to one of the the positions 3, 4 or 5 of the cyclohexane ring. The hydroxy metabolite was formed preferentially from the (-)-enantiomer, (1S,2S)-tramadol.