Abstract:We have studied the dog model for predicting the oral absorption of deramciclane, a novel anxiolytic compound, as a model acid-labile drug. The absorption profile of deramciclane was studied in man and beagle dogs after administration of conventional capsules and enteric coated tablets. Absorption in dogs pretreated with pentagastrin or saline was also studied after administration of conventional capsules. The in-vitro stability of deramciclane was determined over the pH range 1.2-6.0. The rate of degradation … Show more
“…Beagle dogs have frequently been used as a surrogate to human for the study of drug absorption because of their ability to ingest human‐scale dosage forms and their ease of handling. However, significant differences exist between the oral bioavailability observed in dogs and that observed in humans 16,17. Gastric pH in humans has been evaluated using a variety of methodologies, including orogastric or nasogastric intubation and aspiration, direct measurement via a pH probe in the stomach, and radiotelemetry (e.g., Heidelberg capsule).…”
Section: Introductionmentioning
confidence: 99%
“…However, significant differences exist between the oral bioavailability observed in dogs and that observed in humans. 16,17 Gastric pH in humans has been evaluated using a variety of methodologies, including orogastric or nasogastric intubation and aspiration, direct measurement via a pH probe in the stomach, and radiotelemetry (e.g., Heidelberg capsule). Regardless of the method used, fasting gastric pH in humans has been reported to be less than 3.…”
“…Beagle dogs have frequently been used as a surrogate to human for the study of drug absorption because of their ability to ingest human‐scale dosage forms and their ease of handling. However, significant differences exist between the oral bioavailability observed in dogs and that observed in humans 16,17. Gastric pH in humans has been evaluated using a variety of methodologies, including orogastric or nasogastric intubation and aspiration, direct measurement via a pH probe in the stomach, and radiotelemetry (e.g., Heidelberg capsule).…”
Section: Introductionmentioning
confidence: 99%
“…However, significant differences exist between the oral bioavailability observed in dogs and that observed in humans. 16,17 Gastric pH in humans has been evaluated using a variety of methodologies, including orogastric or nasogastric intubation and aspiration, direct measurement via a pH probe in the stomach, and radiotelemetry (e.g., Heidelberg capsule). Regardless of the method used, fasting gastric pH in humans has been reported to be less than 3.…”
“…Formulation 5: Formulation 4 administered to dogs that were pre-treated orally with 4 ml/kg 0.1 N HCl. * = Significantly different from all other treatment groups, p50.01, one-way ANOVA with Bonferroni multiple comparisons post-test co-workers [18]. To avoid the ambiguity of this indirect approach in the present investigation, the pH of the fasted dog stomach was manipulated directly.…”
Section: Discussionmentioning
confidence: 98%
“…To attempt to normalize the pH of the fasted dog stomach to that of other preclinical species and of human, various investigators have attempted to artificially decrease the dog stomach pH. Knupp and colleagues [17] successfully pretreated dogs with pentagastrin to stimulate HCl release, while the same technique proved variable and unsuccessful in a study by Kanerva and co-workers [18]. To avoid the ambiguity of this indirect approach in the present investigation, the pH of the fasted dog stomach was manipulated directly.…”
The endothelins (ET) are among the most potent vasoconstrictors identified to date, and have been implicated in such diseases as renal failure, pulmonary hypertension, atherosclerosis, and congestive heart failure. There is currently interest in developing selective antagonists of the ET-A subtype receptor, and one such antagonist is SB-247083 ((E)-[1-butyl-5-[2-(2-carboxyphenyl) methoxy-4-chlorophenyl]-1H-pyrazole-4-yl]-2-[5-methoxydihydrobenzofuran-6-yl]methyl]-2-propionic acid). This investigation was conducted to evaluate the preclinical pharmacokinetics of SB-247083. Clearance of SB-247083 was low to moderate in the rat and monkey, and high in the dog. Oral bioavailability of SB-247083 administered as a solid formulation of the free acid was 24% in the rat, but low in the dog (4%) and the monkey (2%). An extensive in vitro salt form and formulation screen resulted in the identification of a formulation containing the monoarginyl salt with improved dissolution properties. This formulation provided a 2- to 4-fold increase in oral bioavailability in each of the preclinical species. In the dog, this improvement was reversed by the pre-administration of 0.1 N HCl to normalize the achlorhydric fasting dog stomach. These data show that SB-247083 may have suitable drug properties for progression in development.
“…[2][3][4] Previously published pharmacokinetic studies in several different species, including man, have shown extensive metabolism, with cleavage of the side chain the major metabolic pathway. [5][6][7][8][9][10] The resulting metabolite and derivatives show increased distribution and significant plasma levels for a longer biological half-life than the parent compound. 11,12 Two tritium labelled forms of deramciclane were required with the label in the camphor skeleton, ([3-3 H]deramciclane (3)) and the side chain ([2-dimethylamino-[2-3 H]ethoxy]deramciclane (9)) for in vitro and in vivo studies to further investigate various aspects of the metabolism and pharmacokinetics of deramciclane.…”
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