An in Vitro Digestion Test That Reflects Rat Intestinal Conditions To Probe the Importance of Formulation Digestion vs First Pass Metabolism in Danazol Bioavailability from Lipid Based Formulations

Abstract

The impact of gastrointestinal (GI) processing and first pass metabolism on danazol oral bioavailability (BA) was evaluated after administration of self-emulsifying drug delivery systems (SEDDS) in the rat. Danazol absolute BA was determined following oral and intraduodenal (ID) administration of LFCS class IIIA medium chain (MC) formulations at high (SEDDSH-III) and low (SEDDSL-III) drug loading and a lipid free LFCS class IV formulation (SEDDS-IV). Experiments were conducted in the presence and absence of ABT (1-aminobenzotriazole) to evaluate the effect of first pass metabolism. A series of modified in vitro lipolysis tests were developed to better understand the in vivo processing of SEDDS in the rat. Danazol BA was low (<13%) following oral and ID administration of either SEDDS. Increasing drug loading, ID rather than oral administration, and administration of SEDDS-IV rather than SEDDS-III led to higher oral BA. After pretreatment with ABT, however, danazol oral BA significantly increased (e.g., 60% compared to 2% after administration of SEDDSL-III), no effect was observed on increasing drug loading, and differences between SEDDS-III and -IV were minimal. In vitro digestion models based on the lower enzyme activity and lower dilution conditions expected in the rat resulted in significantly reduced danazol precipitation from SEDDS-III or SEDDS-IV on initiation of digestion. At the doses administered here (4-8 mg/kg), the primary limitation to danazol oral BA in the rat was first pass metabolism, and the fraction absorbed was >45% after oral administration of SEDDS-III or SEDDS-IV. In contrast, previous studies in dogs suggest that danazol BA is less dependent on first pass metabolism and more sensitive to changes in formulation processing. In vitro digestion models based on likely rat GI conditions suggest less drug precipitation on formulation digestion when compared to equivalent dog models, consistent with the increases in in vivo exposure (fraction absorbed) seen here in ABT-pretreated rats.

Chain length affects pancreatic lipase activity and the extent and pH–time profile of triglyceride lipolysis

“…This change consisted in decreasing the pH of the buffer from 7.40 to 6.80 to achieve maximum pseudo-physiological conditions [18]. The lipolysis medium contained 50 mM Trizma Ò maleate [35,36,42,43], 150 mM sodium chloride, 5 mM calcium chloride, 5 mM sodium taurocholate, and 1.25 mM L-a-lecithin. The pH of the medium was adjusted to 6.80 ± 0.05 at 37°C using 1 M NaOH solution as titrant, and a pH-stat titrator unit (T50 Graphix, Mettler Toledo Inc., Leicester, UK) coupled to a pH-electrode (DGi111-SC, Mettler Toledo Inc., Leicester, UK).…”

Untitled

“…This lymphatic system mediated absorption is beneficial for drugs which display high first-pass effect. [32] Readers are directed to some excellent reviews on this subject published elsewhere. [33]…”

Sistemas de entrega de fármacos autoemulsificables: una plataforma de desarrollo alternativa para la industria farmacéutica colombiana

“…Sin embargo, la mayor parte del proceso de digestión se lleva a cabo en el intestino delgado donde la lipasa pancreática continúa con la hidrólisis de los triglicéridos. La presencia de lípidos exógenos en el duodeno estimula la secreción de lípidos biliares (sales biliares, fosfolípidos y colesterol [44], los cuales se combinan con los productos de la digestión previamente obtenidos para generar una serie de estructuras coloidales, que incluyen micelas, micelas mezcladas y vesículas. La solubilización y la capacidad de absorción del intestino delgado de fármacos se potencian significativamente debido a estos metabolitos lipídicos formados, ya que estos facilitan la absorción a través de la pared intestinal por diversos mecanismos para permitir al fármaco llegar a la circulación sistémica y poder ejercer su efecto terapéutico [19,36,43].…”

“…La figura 3 muestra un modelo de lipólisis dinámica propuesto para probar la solubilización de un fármaco a medida que avanza la degradación enzimática de las formulaciones lipídicas. Cabe resaltar que el motivo principal para usar este sistema, en lugar del aparato de disolución establecido en la Farmacopea de Estados Unidos (USP), es que se evalúa la precipitación del fármaco y no la disolución ya que los SEDDS evitan la disolución tradicional puesto que el fármaco se encuentra en un estado molecularmente disperso, es decir, en solución en la formulación [35,44]. El montaje experimental consiste en un recipiente de reacción de doble pared termostatizado, un pH-stat, con una autobureta para la adición de NaOH, una bomba peristáltica para la adición de CaCl 2 , y un computador con un software para los experimentos de titulación.…”