Intestinal permeability and excretion into bile control the arrival of amlodipine into the systemic circulation after oral administration

Raušl, Dragica; Fotaki, Nikoletta; Zanoski, Ruzica; Vertzoni, Maria; Cetina-Čižmek, Biserka; Khan, M. Z. I.

doi:10.1211/jpp.58.6.0013

Cited by 17 publications

(12 citation statements)

References 35 publications

(46 reference statements)

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“…P app values for amlodipine closely mimic those observed by Rausl et al62 from both A–B and B–A. Atorvastatin P app values and efflux ratios are similar to those reported by Wu et al63 An efflux ratio of 1.14 for amlodipine indicates passive diffusion of the compound across Caco-2 monolayers, whereas an efflux ratio of 5.02 for atorvastatin suggests active efflux of the API in the B–A direction.…”

Section: Resultssupporting

confidence: 86%

Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability

Dennison¹,

Smith²,

Badhan³

et al. 2017

DDDT

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Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (Papp) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (<30 s) while displaying a radial crushing strength in excess of 100 N and friability ≤1%. In vitro dissolution test was performed in fasted and fed-state simulated intestinal fluid (FeSSIF) and analyzed using high-performance liquid chromatography. Dissolution profiles for single and FDC ODTs were compared using US FDA recommended difference (f1) and similarity (f2) factor testing for bioequivalence. In all cases, there was no difference in active pharmaceutical ingredient dissolution between single or FDC ODTs, with the exception of amlodipine in FeSSIF. Pharmacokinetic clinical trial simulations were conducted using Simcyp (Version 14), incorporating Papp and dissolution data. Simulated clinical trials in healthy volunteers showed no difference in bioavailability based on pharmacokinetic parameters between single and combination doses with either active pharmaceutical ingredient. An increase in Cmax and AUC for atorvastatin in fed subjects was attributed to extended transit along the gut lumen and reduced atorvastatin metabolism due to lower CYP3A4 expression at more distal small intestine absorption sites. The results demonstrated bioequivalence of an FDC ODT for amlodipine and atorvastatin, while highlighting several limitations of f1 and f2 bioequivalence testing and strengths of mechanistic pharmacokinetic modeling for oral drug absorption.

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Section: Resultssupporting

confidence: 86%

Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability

Dennison¹,

Smith²,

Badhan³

et al. 2017

DDDT

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“…As expected, many compounds with intermediate to high passive P e , low metabolic CL int and efflux have the typical EHC plasma concentration vs time profile (multiple-peaks) in man. Examples include amlodipine (Raušl et al 2006), warfarin and cardiac glycosides (digoxin; MDR1-and OATP-substrate) (Roberts et al 2002;TP-search transport database, 2007). Morphine (moderate P e ; MDR1-substrate; significantly conjugated; deconjugation potential in the intestine) and indometacin (high P e ; MDR1-substrate; low CL int ) have also been shown to undergo some degree of EHC in man (Roberts et al 2002;TP-search transport database, 2007).…”

Section: Predictions In Manmentioning

confidence: 99%

Prediction of human pharmacokinetics—biliary and intestinal clearance and enterohepatic circulation

Fagerholm

2008

Journal of Pharmacy and Pharmacology

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The main objective was to evaluate and propose methods for predicting biliary clearance (CL bile ) and enterohepatic circulation (EHC) of intact drugs in man. Another aim was to evaluate to role of intestinal drug secretion and propose a method for prediction of intestinal secretion CL (CL i ). Animal data poorly predict the CL and CL bile of biliary excreted drugs, and the suggested molecular weight threshold for bile excretion as the dominant elimination route does not seem to hold. Active transport, low metabolic intrinsic CL (CL int ) and, as an approximation, permeability (P e ) less than that of metoprolol is required for substantial CL bile to occur. The typical EHC plasma concentration vs time profile (multiple peaks) is demonstrated for many low metabolic CL int -compounds with efflux and moderate to high intestinal P e and fraction absorbed. Physiologically-based in-vitro to in-vivo (PB-IVIV) methodology with in-vitro intrinsic CL bile -data obtained with sandwich-cultured human hepatocytes has generated 2-and 5-fold underpredictions for two compounds with intermediate to high CL bile . This is despite not considering the unbound fraction. Possible explanations include low transporter activity and diffusion limitations in the in-vitro experiments. Intestinal reabsorption and EHC were also neglected in these predictions and in-vivo CL bile estimations. The sandwich model and these reference data are still very useful. Consideration of an empirical scaling factor and a newly developed approach that accounts for intestinal reabsorption and EHC could potentially lead to improved PB-IVIV predictions of CL bile . Apparently, no attempts have been made to predict CL i . Elimination via the intestinal route does not appear to be of great importance for the few compounds with available data, but could be equally as important as bile excretion. Net secretion in-vitro P e and newly estimated in-vivo intrinsic CL i data for digoxin and rosuvastatin could be useful for approximation of CL i of other compounds.

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“…Equation (3) was used to calculate F a if all the data were available (Prediction B). For drugs lacking in vivo data in humans to calculate the F a value, so long as the in vivo human jejunal permeability (P eff,man ) or the in vitro permeability across Caco-2 monolayer (P eff ) were available from literature [7][8][9][10][11][12], the F a value was predicted by using a physiologically based population pharmacokinetic simulator (Simcyp Ver 12, Sheffield, UK) (Prediction B, likewise).…”

Section: Calculation Of Auc Ratiosmentioning

confidence: 99%

Prediction of the extent and variation of grapefruit juice–drug interactions from the pharmacokinetic profile in the absence of grapefruit juice

Kogure

Akiyoshi

Imaoka

et al. 2014

Biopharm & Drug Disp

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The aim of this study was to develop a method for predicting the extent of grapefruit juice (GFJ)-drug interactions and their interindividual variations from the pharmacokinetic profile in the absence of GFJ. The pharmacokinetic profiles of 13 drugs after intravenous and oral administration were used to develop and validate the method. For each drug, the proportion absorbed into the intestine and the intestinal availability (Fg ) were calculated from clinical data taken from the literature. Then, the AUC ratio (the ratio of the AUC with GFJ to that without GFJ) was predicted by assuming that Fg was 1.0 when GFJ was concomitantly ingested. According to the developed method, the AUC ratio of felodipine was 2.50 and its coefficient of variation (CV) was 45%, which agreed well with the observed AUC ratio of 2.48 and CV of 51%. Although the developed method overestimated the AUC ratios of some drugs such as nisoldipine, no underestimation occurred. The predicted CV values were consistent with those observed. The developed method might be useful to predict the AUC ratio, along with its interindividual variation, from the pharmacokinetic profile in the absence of grapefruit juice.

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Intestinal permeability and excretion into bile control the arrival of amlodipine into the systemic circulation after oral administration

Cited by 17 publications

References 35 publications

Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability

Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability

Prediction of human pharmacokinetics—biliary and intestinal clearance and enterohepatic circulation

Prediction of the extent and variation of grapefruit juice–drug interactions from the pharmacokinetic profile in the absence of grapefruit juice

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