Dose-independent pharmacokinetics of a candidate for diabetic neuropathy, SR-4668, after intravenous and oral administration to rats: Intestinal first-pass effect

Modern drug discovery has led to the development of drug molecules that exhibit high lipophilicity and poor water solubility, which leads to problematic bioavailability. Approaches have thus been made to enhance dissolution of poorly water soluble drugs through modifications and creation of specific formulations. Metaclopramide is an antiemetic and gastroprokinetic agent, commonly used to treat nausea and vomiting. It is absorbed well after oral administration but a significant first pass effect in some human patients may reduce systemic bioavailability to 30%.The Metaclopramide base is thus modified from Metaclopramide hydrochloride to enhance solubility .This has been achieved by the formulating in solid dispersion since Metaclopramide is poorly water soluble. Though it is absorbed well after oral administration, a significant first pass effect in some patients reduces systemic bioavailability, which can cause adverse side effects. This solid dispersion has then been used through transdermal drug delivery. Enhancement of solubility of poorly water soluble drug by solid dispersion may be attributed to particles modified characters such as particle size reduction, improved wettability, higher porosity, decreased lattice energy, amorphous state. The main objective thus includes modification of drug Metaclopramide hydrochloride to Metaclopramide base, preparation of solid dispersion of modified Metaclopramide base drug which has poor water solubility, experimental analysis of Metaclopramide base drug and solid dispersion products with carriers. Keywords: solubility, Metaclopramide, solid dispersion, carriers, HPβCD, PVP K-30

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Erratum to “Absorption, liver first-pass effect, pharmacokinetics and tissue distribution of calycosin-7-O-ß-d-glucopyranoside (C7G) and its major active metabolite, calycosin, following oral administration of C7G in rats by LC–MS/MS” [J. Pharm. Biomed. Anal. 148 (2018) 350–354]

Journal of Pharmaceutical and Biomedical Analysis ◽

10.1016/j.jpba.2018.01.003 ◽

2018 ◽

Vol 150 ◽

pp. 474

Author(s):

Xiaoting Tian ◽

Shuoji Chen ◽

Yuanyuan Zhang ◽

Luying Chen ◽

Xiaozhen Guo ◽

...

Keyword(s):

Oral Administration ◽

Tissue Distribution ◽

Active Metabolite ◽

First Pass Effect ◽

First Pass ◽

Pharm Biomed Anal

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Dose-Dependent Pharmacokinetics of Tofacitinib in Rats: Influence of Hepatic and Intestinal First-Pass Metabolism

Pharmaceutics ◽

10.3390/pharmaceutics11070318 ◽

2019 ◽

Vol 11 (7) ◽

pp. 318 ◽

Cited By ~ 4

Author(s):

Ji Sang Lee ◽

So Hee Kim

Keyword(s):

Oral Administration ◽

Intravenous Administration ◽

Hepatic Metabolism ◽

Time Curve ◽

First Pass Effect ◽

First Pass Metabolism ◽

First Pass ◽

Dose Dependent ◽

Intraduodenal Administration ◽

Pass Metabolism

This study investigated the pharmacokinetics of tofacitinib in rats and the effects of first-pass metabolism on tofacitinib pharmacokinetics. Intravenous administration of 5, 10, 20, and 50 mg/kg tofacitinib showed that the dose-normalized area under the plasma concentration-time curve from time zero to infinity (AUC) was significantly higher at 50 mg/kg than at lower doses, a difference possibly due to saturation of the hepatic metabolism of tofacitinib. Oral administration of 10, 20, 50, and 100 mg/kg tofacitinib showed that the dose-normalized AUC was significantly higher at 100 mg/kg than at lower doses, a difference possibly due to saturation of the intestinal metabolism of tofacitinib. Following oral administration of 10 mg/kg tofacitinib, the unabsorbed fraction from the rat intestine was 3.16% and the bioavailability (F) was 29.1%. The AUC was significantly lower (49.3%) after intraduodenal, compared to intraportal, administration, but did not differ between intragastric and intraduodenal administration, suggesting that approximately 46.1% of orally administered tofacitinib was metabolized through an intestinal first-pass effect. The AUC was also significantly lower (42%) after intraportal, compared to intravenous, administration, suggesting that the hepatic first-pass effect on tofacitinib after entering the portal vein was approximately 21.3% of the oral dose. Taken together, these findings suggest that the low F of tofacitinib is due primarily to intestinal first-pass metabolism.

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