Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure—Pharmacokinetic relationships

Isradipine related to dihydropyridine (DHP) class of calcium channel blockers (CCBs). It is used to treat hypertension, angina pectoris, as well as Parkinson disease. It goes under the BCS class II drug (low solubility-high permeability). The drug will experience extensive first-pass metabolism in liver, thus, oral bio-availability will be approximately15 to 24 %. The aim of the study is preparing stable oral oil in water (o/w) nanoemulsion of isradipine to promote the colloidial dispersion of isradipine in the nano range, so that it may be absorded by intestinal lymphatic transport in order to avoid hepatic first-pass metabolism (israpidine undergoes 15-24% first pass metabolism) and increase drug bioavailability. The solubility study was carried out in various vehicles for selecting best solvent for dissolving isradipine. Pseudo-ternary phase diagrams is formed at (1:1, 1:2, 1:3, 1:4 and 2:1) ratios related to Smix (co-surfactant and surfactant). There are 11 nano-emulsion was prepared through the use of many concentrations of ( Transcutol, Tween20, and Triacetin). All formulations assessed for (in-vitro drug dissolution, pH measurement, viscosity, drug content, polydispersity index, particle size distribution, thermodynamic stability, dye test, and light transmittance). It is indicated that the extent as well as the rate of release regarding all the prepared formulations have considerably higher in comparison to that of crude drug powder. Results of characterization were explained that isradipine nano emulsion (NE9) with S mix(1:4) : oil : deionized water (40: 5: 55) ratio was the optimized formula that has droplet size range (177.1nm), the lowest value of polydispersity index (0.12), the highest percent of drug content (99.7%) typical pH value for oral administration (5.21) , good percent of light transmittance (99.86 %), the range of viscosity (65.12 -25.2 m Pas. sec.) was suitable for oral administration, also the isradipine’s in vitro release has been considerably higher. It can be concluded that nano emulsion drug delivery system (DDS) can be considered as an encouraging method for improving the stability, dissolution and solubility of formulation. Keywords: Nanoemulsion, Isradipine , Peudoternary phase diagrams.

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Pharmacokinetic Modeling of M6G Formation after Oral Administration of Morphine in Healthy Volunteers

Anesthesiology ◽

10.1097/00000542-199904000-00016 ◽

1999 ◽

Vol 90 (4) ◽

pp. 1026-1038 ◽

Cited By ~ 37

Author(s):

Jorn Lotsch ◽

Michel Weiss ◽

Gabi Ahne ◽

Gerd Kobal ◽

Gerd Geisslinger

Keyword(s):

Oral Administration ◽

Current Model ◽

Oral Morphine ◽

Oral Dosing ◽

Effect Site ◽

Morphine Administration ◽

First Pass Metabolism ◽

First Pass ◽

Pass Metabolism

Background Morphine is metabolized to two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide (M6G). Under the conditions of long-term oral morphine administration, the accumulation of M6G may contribute to the analgesic effects, but it may also cause respiratory depression. Methods Five healthy male volunteers (ages 25-34 yr) received 90 mg MST (morphine sulfate 5H2O sustained-released tablet, equivalent to 67.8 mg oral morphine). Multiple plasma and urine samples were taken for as long as 14 and 36 h, respectively. Individual pharmacokinetics after intravenous administration of morphine and M6G were available from a previous investigation. A new model that considers the M6G-plasma profile as a sum of the input from the first-pass metabolism of morphine and the input from systemically available morphine was applied to the plasma concentration versus time curves of M6G. The concentrations of M6G at the effect site after long-term morphine administration were simulated. Results The fraction of morphine absorbed from the gut was 82+/-14%. Of this, 42+/-8% passed through the liver, resulting in an oral bioavailability of morphine of 34+/-9%. Of the total amount of M6G, 71+/-7% was formed during the first-pass metabolism, and 29+/-7% was formed by metabolism of systemic morphine. After 36 h, the amounts of M6G and morphine excreted in the urine were 92+/-17% and 9+/-3%, respectively. Simulation of effect-site concentrations of M6G indicated that after multiple oral dosing of morphine in patients with normal liver and renal function, M6G might reach concentrations two times greater than that of morphine. Conclusions M6G may contribute to the analgesic and side effects seen with long-term morphine treatment. The current model of morphine and M6G pharmacokinetics after oral administration of morphine may serve as a pharmacokinetic basis for experiments evaluating the analgesic contribution of M6G with long-term oral dosing of morphine.

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Reduction of first-pass metabolism of propranolol after oral administration of ester prodrugs

International Journal of Pharmaceutics ◽

10.1016/0378-5173(88)90283-9 ◽

1988 ◽

Vol 43 (3) ◽

pp. 261-265 ◽

Cited By ~ 15

Author(s):

B.D. Anderson ◽

W.W. Chu ◽

R.E. Galinsky

Keyword(s):

Oral Administration ◽

First Pass Metabolism ◽

First Pass ◽

Ester Prodrugs ◽

Pass Metabolism

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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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Identification of a Cranberry Juice Product Capable of Inhibiting Enteric CYP3A-Mediated First-Pass Metabolism in Humans

Planta Medica ◽

10.1055/s-2008-1075176 ◽

2008 ◽

Vol 74 (03) ◽

Author(s):

N Ngo ◽

Z Yan ◽

TN Graf ◽

DR Carrizosa ◽

EC Dees ◽

...

Keyword(s):

Cranberry Juice ◽

First Pass Metabolism ◽

First Pass ◽

Pass Metabolism

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Development, Characterization and Optimization of Mucoadhesive Tablet for Buccal Delivery of Domperidone

Drug Delivery Letters ◽

10.2174/2210303108666181108120840 ◽

2019 ◽

Vol 9 (1) ◽

pp. 37-49

Author(s):

Jagdale Sachin ◽

Panbude Aishwarya ◽

Navasare Priya

Keyword(s):

Drug Release ◽

Factorial Design ◽

Research Work ◽

Wet Granulation ◽

Buccal Delivery ◽

Scanning Calorimetry ◽

Mucoadhesive Polymers ◽

First Pass Metabolism ◽

First Pass ◽

Pass Metabolism

Background and Objective: Upon oral administration domeperidone is rapidly absorbed, but subjected to the first pass effect which lowers systemic bioavailability to 15%. Mucoadhesive tablet can remain attached to buccal mucosa and becomes capable of bypassing hepatic first-pass metabolism to improve absorption directly into systemic circulation. The present research work was carried with an aim to develop, evaluate and optimize mucoadhesive tablet containing domperidone (DOME) for buccal delivery using different bio-adhesive polymeric combinations. </P><P> Methods: The buccal tablets were formulated by wet granulation method using isopropyl alcohol. The preliminary formulations were prepared using combinations of HPMC K4, HPMC K15, HPMC K100, HPMC E5 as mucoadhesive polymers. 32 full factorial design was applied to determine the effect of independent variables like concentration of mucoadhesive polymers (HPMC K15 and HPMC K100) over dependent variables like mucoadhesive properties (swelling index, bioadhesive strength and in vitro drug release). The prepared mucoadhesive tablets were evaluated for their tablet properties and mucoadhesive properties. The interactions between drug and polymers were studied by Fourier Transform Infrared Spectroscopy (FTIR) and Differential Scanning Calorimetry (DSC). </P><P> Results: All formulations of factorial design showed satisfactory physicochemical, mechanical and bioadhesive characteristics. The formulation F9 exhibited maximum cumulative drug release, mucoadhesive strength and swelling index. Conclusion: The developed buccal tablet of domperidone might prove alternative to bypass the hepatic first pass metabolism and to avoid degradation which in turn may result in reducing the frequency of administration. Thus, mucoadhesive tablet of domeperidone may become viable alternative overcoming the side effects; achieving greater therapeutic effectiveness and improving the patient compliance.

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