Resumen
98%
Farmacocinética
|
0% | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Albendazol |
Puntuaciones | 0% | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Extensión de tiempo QT
| |||||||||||
Efectos anticolinérgicos
| |||||||||||
Efectos serotoninérgicos
|
Efectos adversos de las drogas
|
-2% | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Dolor de cabeza | |||||||||||
Alopecia | |||||||||||
Dolor abdominal |
Variantes ✨
Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Farmacocinética
-0%
∑ Exposicióna | alb | |
---|---|---|
Albendazol | 1 |
Leyenda (n.a.): Información no disponible
Dado que solo se introdujo albendazol sin otras sustancias, no se pueden detectar interacciones farmacocinéticas.
Clasificación:
Los parámetros farmacocinéticos de la población media se utilizan como punto de partida para calcular los cambios individuales en la exposición debidos a las interacciones.
Se desconoce la biodisponibilidad de albendazol. Se desconoce la unión a proteínas [Pb]. El metabolismo tiene lugar a través de CYP2C19 y CYP3A4, entre otros..
Efectos serotoninérgicos
-0%
Puntuaciones | ∑ Puntos | alb |
---|---|---|
Efectos serotoninérgicos a | 0 | Ø |
Clasificación: Según nuestro conocimiento, la albendazol no aumenta la actividad serotoninérgica.
Efectos anticolinérgicos
-0%
Puntuaciones | ∑ Puntos | alb |
---|---|---|
Kiesel b | 0 | Ø |
Clasificación: Según nuestros hallazgos, la albendazol no aumenta la actividad anticolinérgica.
Extensión de tiempo QT
-0%
No conocemos ningún potencial de prolongación del intervalo QT para la albendazol.
Efectos secundarios generales
-2%
Efectos secundarios | ∑ frecuencia | alb |
---|---|---|
Dolor de cabeza | 11.0 % | 11.0 |
Alopecia | 1.0 % | + |
Dolor abdominal | 1.0 % | + |
Náusea | 1.0 % | + |
Leucopenia | 0.7 % | 0.7 |
Eritema multiforme | 0.0 % | 0.0 |
Síndrome de Stevens-Johnson | 0.0 % | 0.0 |
Pancreatitis | 0.0 % | 0.0 |
Hepatitis | 0.0 % | 0.1 |
Signo (+): efecto adverso descrito, pero frecuencia no conocida
Signo (↑/↓): frecuencia bastante más alta / más baja debido a la exposición
Limitaciones
Con base en sus
Referencias de literatura
Abstract: AIMS: Albendazole (ABZ; methyl 5-propylthio-1H-benzimidazol-2-yl carbamate) is a broad spectrum anthelmintic whose activity resides both in the parent compound and its sulphoxide metabolite (ABS). There are numerous reports of ABZ metabolism in animals but relatively few in humans. We have investigated the sulphoxidation of ABZ in human liver microsomes and recombinant systems. METHODS: The specific enzymes involved in the sulphoxidation of ABZ were determined by a combination of approaches; inhibition with an antiserum directed against cytochrome P450 reductase, the effect of selective chemical inhibitors on ABZ sulphoxidation in human liver microsomes, the capability of expressed CYP and FMO to mediate the formation of ABS, regression analysis of the rate of metabolism of ABZ to ABS in human liver microsomes against selective P450 substrates and regression analysis of the rate of ABS sulphoxidation against CYP expression measured by Western blotting. RESULTS: Comparison of Vmax values obtained following heat inactivation (3min at 45 degrees C) of flavin monoxygenases (FMO), chemical inhibition of FMO with methimazole and addition of an antiserum directed against cytochrome P450 reductase indicate that FMO and CYP contribute approximately 30% and 70%, respectively, to ABS production in vitro. Comparison of CLint values suggests CYP is a major contributor in vivo. A significant reduction in ABZ sulphoxidation (n = 3) was seen with ketoconazole (CYP3 A4; 32-37%), ritonavir (CYP3 A4: 34-42%), methimazole (FMO: 28-49%) and thioacetamide (FMO; 32-35%). Additive inhibition with ketoconazole and methimazole was 69 +/- 8% (n = 3). ABS production in heat - treated microsomes (3 min at 45 degrees C) correlated significantly with testosterone 6beta-hydroxylation (CYP3A4; P < 0.05) and band intensities on Western blots probed with an antibody selective for 3A4 (P < 0.05). Recombinant human CYP3 A4, CYP1A2 and FMO3 produced ABS in greater quantities than control microsomes, with those expressing CYP3A4 producing threefold more ABS than those expressing CYP1A2. Kinetic studies showed the Km values obtained with both CYP3A4 and FMO3 were similar. CONCLUSIONS: We conclude that the production of ABS in human liver is mediated via both FMO and CYP, principally CYP3A4, with the CYP component being the major contributor.
Abstract: Albendazole is a clinically important anthelminthic agent known to have variable and low oral bioavailability. The aim of this work was to determine whether albendazole, a CYP3A4 substrate, is also a substrate for the multidrug efflux transporter P-glycoprotein. Both in vitro and in vivo methods were used to assess the role of P-glycoprotein-mediated albendazole transport. In cultured LLC-PK1, L-MDR1, and Caco-2 cells, albendazole was found not to be a P-glycoprotein substrate; the transport across LLC-PK1 and L-MDR1 cells revealed basal to apical versus apical to basal transport to a similar extent. In addition, there was no inhibitory effect of albendazole on digoxin transport in Caco-2 cells, and P-glycoprotein inhibitors (verapamil and quinidine) did not affect transport across Caco-2 cells. The in vivo relevance of P-glycoprotein to albendazole disposition was assessed using mdr1a/1b(-/-) mice after intravenous administration of albendazole (15 mg/kg). A similar pattern of tissue distribution in both P-glycoprotein-deficient and wild-type mice was observed. In conclusion, albendazole is neither a substrate nor an inhibitor of P-glycoprotein. Therefore, interactions between albendazole and P-glycoprotein substrates or inhibitors are unlikely to be clinically important.
Abstract: Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 μl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 μl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo.