RESUMEN
The new 5-hydroxytryptamine type 3 (5HT3) receptor antagonist tropisetron is used in the treatment of chemotherapy-related nausea. The drug is extensively metabolized in man, with the enzymes involved in tropisetron biotransformation being unknown. Identification of these enzymes would make it possible to predict both interindividual variability in plasma concentrations and metabolic interaction potential. The present in vitro study was therefore aimed at identifying and characterizing the cytochrome P450 enzymes catalysing tropisetron metabolism. Enzyme kinetics for formation of 5-hydroxy (5-OH-ICS), 6-hydroxy (6-OH-ICS) and N-demethyl tropisetron (N-De-ICS) were studied in the microsomal fraction of eight human livers (seven livers from extensive metabolizer (EM), one liver from a poor metabolizer (PM) for CYP2D6). Formation of 5-OH-ICS and 6-OH-ICS was biphasic with a high (5-OH: Km 3.9 +/- 2.1 microM; Vmax 1.88 +/- 0.73 pmol/mg/min; 6-OH: Km 4.66 +/- 1.84 microM; Vmax 4.00 +/- 1.77 pmol/mg/min) and low (5-OH: Km 172 +/- 51 microM; Vmax 17.0 +/- 9.4 pmol/mg/min; 6-OH: Km 266.0 +/- 76.0 microM; Vmax 81.4 +/- 27.9 pmol/mg/min) affinity component. The high-affinity component was identified as CYP2D6 which exhibits a genetic polymorphism in man. This component was absent in the PM liver. The low-affinity component was present in EM and PM livers and was identified as CYP3A4. LKM1 antibodies directed against CYP2D6 completely inhibited the high affinity component. Quinidine (0.5 microM) inhibited 5- and 6-hydroxylation at 10-80 microM tropisetron concentrations competitively by 70% with Ki values of 10 and 18 nM, respectively. Stably-expressed CYP2D6 catalysed the formation of both 5-OH-ICS and 6-OH-ICS. Both inhibition experiments and use of stably-expressed enzymes revealed formation of N-De-ICS to be mediated by CYP3A4. Based on in vitro intrinsic clearances CYP2D6-catalysed 5-OH-ICS and 6-OH-ICS is the predominant route of tropisetron elimination. Large phenotype-related differences in total clearance are to be expected after administration of tropisetron. However, in view of the wide therapeutic index of tropisetrone and the rather high Ki for inhibition of the metabolism of other drugs by tropisetron, both the interindividual variability and the interaction potential appear to be of no clinical relevance.
Asunto(s)
Antieméticos/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Indoles/metabolismo , Isoenzimas/metabolismo , Catálisis , Clonación Molecular , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/genética , Humanos , Técnicas In Vitro , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Cinética , Microsomas Hepáticos/enzimología , Quinidina/farmacología , TropisetrónRESUMEN
The plasma concentrations of the tetracyclic antidepressant maprotiline and its effect on histamine-induced bronchoconstriction were measured after single (50 mg) and multiple (50 mg twice daily) oral doses in healthy subjects. Histamine-induced bronchoconstriction was abolished after a single dose of maprotiline and this effect persisted throughout multiple dose treatment. The mean Cmax of maprotiline in six poor metabolisers (PM) of debrisoquine was 2.7-fold greater than that in six extensive metabolisers (EM) and the mean AUC(0,48 h) was 3.5 times higher. The duration of the pulmonary effect of maprotiline after cessation of multiple dose treatment in EM was less than 3 weeks compared with at least 4 weeks in PM.
Asunto(s)
Debrisoquina/metabolismo , Antagonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/farmacocinética , Maprotilina/farmacología , Maprotilina/farmacocinética , Administración Oral , Adulto , Biotransformación , Broncoconstricción/efectos de los fármacos , Citocromo P-450 CYP2D6 , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Semivida , Histamina/farmacología , Antagonistas de los Receptores Histamínicos/administración & dosificación , Humanos , Hidroxilación , Masculino , Maprotilina/administración & dosificación , Flujo Espiratorio Máximo/efectos de los fármacos , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Polimorfismo GenéticoRESUMEN
The optically active isomers of the racemic tetracyclic antidepressant oxaprotiline, R (-) oxaprotiline CGP 12,103 A (levoprotiline) and the S (+) oxaprotiline CGP 12,104 A, have been used as tools for a methodological Phase I study. Only the S (+) enantiomer CGP 12,104 A inhibits noradrenaline uptake. Intravenous amine pressor tests and ex vivo measurement of alpha 2-adrenoceptor binding to intact human platelets were compared with respect to their reliability in indicating CGP 12,104 A-induced amine uptake inhibition and possibly associated alpha 2-receptor down-regulation in healthy subjects. alpha 2-Adrenoceptor binding on intact human platelets did not distinguish between CGP 12,104 and CGP 12,103 A. However, amine pressor tests reflected the amine uptake inhibiting effect of CGP 12,104 A as a 5-fold decrease in tyramine pressor sensitivity and a 5-fold increase in noradrenaline pressor sensitivity.
Asunto(s)
Antidepresivos/farmacología , Plaquetas/metabolismo , Presión Sanguínea/efectos de los fármacos , Maprotilina/análogos & derivados , Norepinefrina/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Adulto , Depresión Química , Femenino , Humanos , Técnicas In Vitro , Masculino , Maprotilina/farmacología , Unión Proteica , Método Simple Ciego , Estereoisomerismo , TiraminaRESUMEN
The pressor effect of intravenous tyramine (TYR) and noradrenaline (NA) has been evaluated, respectively, in 157 tests in 19 healthy unmedicated subjects, and in 202 tests in 24 similar subjects, all of whom took part in greater than or equal to 3 test sessions. The pressor dose (PD) that raised systolic blood pressure by 30 mm Hg (PD30) ranged from 2 to 8 mg for TYR, and from 3.5 to 17 micrograms.min-1 for NA. Coefficients of variation ranged from 3 to 47% and from 6 to 38% for TYR and NA, respectively, in the intra-subject comparison. The average inter-subject variation in the TYR PD30 was 22% for 8 females and 30% for 11 males; the corresponding variation in the NA PD30 was 27% (8 females) and 26% (16 males). While the average PD30 for NA was similar for males (10.8 micrograms/min) and females (10.9 micrograms/min), a sex-related difference was found for the PD30 of i.v. TYR: 4.4 mg for 11 males and 3.8 mg for 8 females. Additional results from volunteers who took part in fewer than 3 pressor test sessions supported this observation; PD30 of TYR 4.6 mg in 34 males vs 3.5 mg in 21 females. The large intra- and inter-subject variations in the i.v. TYR and NA pressor test results, and the sex difference in the systolic blood pressure response to i.v. TYR, should be considered in assessing the number and gender of subjects required in studies intended to show "significant" differences in the blood pressure response in amine pressor tests.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Norepinefrina/farmacología , Tiramina/farmacología , Adolescente , Adulto , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Norepinefrina/administración & dosificación , Reproducibilidad de los Resultados , Factores Sexuales , Tiramina/administración & dosificaciónRESUMEN
The two monoamine oxidase (MAO) inhibitors phenelzine and brofaromine given for 2 to 3 weeks were compared in six volunteers. Blood pressure sensitivity to intravenous tyramine increased 2.6-fold during phenelzine (60 mg/day) and 4.8-fold during brofaromine, whereas sensitivity to oral tyramine increased more during phenelzine (15.7-fold vs 8.5-fold). After withdrawal of phenelzine, pressor sensitivity to oral tyramine returned to control values within 2 and for more than 8 weeks. Relative bioavailability of conjugated tyramine was elevated sixfold by brofaromine and 11.6-fold by phenelzine. Urinary elimination of tryptamine increased during phenelzine and brofaromine to 12.7-fold and threefold, respectively. 3-Methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) excretion decreased during brofaromine significantly by 72% and 49%, respectively. The nonsignificant decrease of MHPG excretion and the increase of intravenous tyramine pressor sensitivity caused by phenelzine are significantly related. The data suggest that the selective reversible MAO-A inhibitor brofaromine has a larger therapeutic safety than phenelzine.