Thiry-Vella Dog as a Biologic Model for Evaluation of Drug Absorption from the Intestinal Mucosa

Sample, R.G.; Rossi, G; Packman, Elias W.

doi:10.1002/jps.2600570515

Cited by 11 publications

(6 citation statements)

References 6 publications

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“…Results of in vivo PK analysis clearly showed that F a F g values of propranolol and acetaminophen in cynomolgus monkeys were markedly lower than those in humans (Figure ). Propranolol was reported to be a substrate of CYP1A2, 2D6, and UGT, – and acetaminophen and naproxen were also the substrate of UGT in humans. Several reports have demonstrated that the intestinal first-pass metabolism of midazolam, a typical substrate of CYP3A, in cynomolgus monkeys is markedly higher than that in humans and is a main factor of the low BA in cynomolgus monkeys. , It was also reported that the conjugative activities in the intestine were higher in cynomolgus monkeys than in humans. , Since the membrane permeability of propranolol and acetaminophen were considered to be high enough, it is obvious that the high first-pass metabolism in the enterocytes is a main factor of their low F a F g in cynomolgus monkeys.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Gastrointestinal Drug Absorption in Cynomolgus Monkeys

et al. 2008

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Possible factors of species differences in gastrointestinal drug absorption between cynomolgus monkeys and humans were examined using several commercial drugs. Oral bioavailability (BA) of acetaminophen, furosemide, and propranolol in cynomolgus monkeys was significantly lower than that in humans. From the pharmacokinetic analysis, these drugs were found to show the low fraction absorbed into portal vein (FaFg), suggesting that the low BA in cynomolgus monkeys was attributed mainly to the gastrointestinal absorption processes. The gastric emptying rate (GER) calculated from plasma concentration profiles after oral administration of acetaminophen in cynomolgus monkeys was similar in humans. The gastrointestinal transit time (GITT) in cynomolgus monkeys was only slightly shorter than that in humans. On the other hand, it was demonstrated that the apparent intestinal permeability (Papp) of five drugs to cynomolgus monkey intestine was lower than that to rat intestine; especially propranolol and furosemide showed the remarkably low Papp. The expression levels of mRNAs of efflux transporters analyzed by real-time RT-PCR indicated that mRNA expression levels of MDR1, MRP2, and BCRP in monkey intestine were significantly higher than those in human intestine. This result suggested that low oral absorption of furosemide in cynomolgus monkeys was attributed to the high activities of efflux transporters in its intestinal membrane. Results of in vivo PK analysis clearly showed that FaFg values of propranolol and acetaminophen in cynomolgus monkeys were markedly lower than those in humans. Since propranolol and acetaminophen were the drug with high membrane permeability, it was considered that the high first-pass metabolism in the enterocytes was a main factor of their low FaFg in cynomolgus monkeys. In conclusion, it was demonstrated that the high activities of efflux transporters and/or metabolizing enzymes in the intestinal membrane are possible factors to cause poor oral absorption of drugs in cynomolgus monkeys.

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Section: Discussionmentioning

confidence: 99%

Characterization of Gastrointestinal Drug Absorption in Cynomolgus Monkeys

et al. 2008

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“…Acetaminophen is one of the markers widely used in measuring gastric emptying, be cause it is safe and is not absorbed from the stomach. It has been reported that almost all the acetaminophen infused into the small in testine was absorbed and the absorbance be gan within several minutes (18). Accordingly, it is thought that the plasma acetaminophen concentration correlates with the amount of acetaminophen emptied from the stomach.…”

Section: Gastric Emptying In the Dogmentioning

confidence: 99%

Stimulatory Effect of N-(4-(2-(Dimethylamino)-ethoxy)benzyl)-3,4-Dimethoxybenzamide Hydrochloride(HSR-803)on Normal and Delayed Gastrointestinal Propulsion.

et al. 1991

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ABSTRACT-To estimate the effect of a new gastroprokinetic agent, N-[4-[2 (dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803), on non-ulcer dyspepsia, the influence of HSR-803 on gastrointestinal propulsion was assayed in dogs, rats and mice in comparison with some gastroprokinetic agents. HSR-803 (30 mg/kg, p.o.) significantly enhanced gastric emptying in dogs, and it sig nificantly improved the delayed gastric emptying induced by dopamine (0.4 mg/kg, i.p.) and morphine (1 mg/kg, s.c.) in rats. Metoclopramide (30 mg/kg, p.o.) also sig nificantly restored the dopamine-induced delay, but at a dose of 10 mg/kg, p.o., it en hanced the morphine-induced delay in gastric emptying in rats. HSR-803 (10 100 mg/kg, p.o.) increased small intestinal transit in mice in a dose-dependent manner, and the effect was abolished by atropine (0.3 mg/kg, i.p.). Metoclopramide also in creased small intestinal transit, but domperidone and cisapride had no effect. In de layed small intestinal transit in mice, HSR-803 (10-100 mg/kg, p.o.) improved the morphine (0.3 mg/kg, s.c.)-induced delay in a dose-dependent manner. In conclusion, because of the promotion of normal and delayed gastrointestinal propulsion, HSR-803 seems to be a promising gastroprokinetic agent for the treatment of non-ulcer dyspep sia. The action of HSR-803 is likely to be exerted through cholinergic stimulation.It has been reported that a new gastropro kinetic agent, HSR-803, stimulates gastrointes tinal motility in conscious dogs, probably through dopamine D2 receptor (D2) blocking and anti-acetylcholinesterase (anti-AChE) ac tivities (1). Several gastroprokinetic agents, metoclopramide and domperidone are known to be D2 antagonists, and reported to have weak anti-AChE activity (1-3). A newly de veloped gastroprokinetic agent, cisapride, also has an anti-D2 action (4). The D2 blocking activity of HSR-803 was weaker than that of metoclopramide, domperidone and cisapride, while anti-AChE activity was more potent than that of metoclopramide and domperidone (5). Thus the pharmacological profile of HSR 803 was expected to differ from that of meto clopramide and domperidone.One of, the gastrointestinal disorders, non ulcer dyspepsia having symptoms of discom fort in the epigastrium, fullness in the abdo men, nausea and emesis is mainly due to de

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“…These results, together with the almost complete absorption of paracetamol when dosed in dogs under fasted state conditions [25], indicates that paracetamol is rapidly and completely absorbed from the upper intestine. It has been further shown that the absorption kinetics of paracetamol are highly dependent on the gastric emptying pattern [26].…”

Section: Paracetamol Studymentioning

confidence: 90%