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The low/high BCS permeability class boundary: physicochemical comparison of metoprolol and labetalol.
Zur, Moran; Gasparini, Marisa; Wolk, Omri; Amidon, Gordon L; Dahan, Arik.
Afiliação
  • Zur M; Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer-Sheva 84105, Israel.
Mol Pharm ; 11(5): 1707-14, 2014 May 05.
Article em En | MEDLINE | ID: mdl-24735251
Although recognized as overly conservative, metoprolol is currently the common low/high BCS permeability class boundary reference compound, while labetalol was suggested as a potential alternative. The purpose of this study was to identify the various characteristics that the optimal marker should exhibit, and to investigate the suitability of labetalol as the permeability class reference drug. Labetalol's BCS solubility class was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in vitro and in vivo in rats, considering the complexity of the whole of the small intestine. Labetalol was found to be unequivocally a high-solubility compound. In the pH range throughout the small intestine (6.5-7.5), labetalol exhibited pH-dependent permeability, with higher permeability at higher pH values. While in vitro octanol-buffer partitioning (Log D) values of labetalol were significantly higher than those of metoprolol, the opposite was evident in the in vitro PAMPA permeability assay. The results of the in vivo perfusion studies in rats lay between the two contradictory in vitro studies; metoprolol was shown to have moderately higher rat intestinal permeability than labetalol. Theoretical distribution of the ionic species of the drugs was in corroboration with the experimental in vitro and the in vivo data. We propose three characteristics that the optimal permeability class reference drug should exhibit: (1) fraction dose absorbed in the range of 90%; (2) the optimal marker drug should be absorbed largely via passive transcellular permeability, with no/negligible carrier-mediated active intestinal transport (influx or efflux); and (3) the optimal marker drug should preferably be nonionizable. The data presented in this paper demonstrate that neither metoprolol nor labetalol can be regarded as optimal low/high-permeability class boundary standard. While metoprolol is too conservative due to its complete absorption, labetalol has been shown to be a substrate for P-gp-mediated efflux transport, and both drugs exhibit significant segmental-dependent permeability along the gastrointestinal tract. Nevertheless, the use of metoprolol as the marker compound does not carry a risk of bioinequivalence: Peff value similar to or higher than metoprolol safely indicates high-permeability classification. On the other hand, a more careful data analysis is needed if labetalol is used as the reference compound.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Labetalol / Metoprolol Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Mol Pharm Assunto da revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Israel

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Labetalol / Metoprolol Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Mol Pharm Assunto da revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Israel