scholarly journals Investigation of the Functional Role of P-Glycoprotein in Limiting the Oral Bioavailability of Lumefantrine

2013 ◽  
Vol 58 (1) ◽  
pp. 489-494 ◽  
Author(s):  
Wahajuddin ◽  
Kanumuri S. R. Raju ◽  
Sheelendra P. Singh ◽  
Isha Taneja
Keyword(s):  
Intestinal Absorption ◽  
Oral Absorption ◽  
Stability Study ◽  
Cytochrome P450 3A ◽  
Glycoprotein P ◽  
Active Efflux ◽  
P Glycoprotein

ABSTRACTIn the quest to explore the reason for the low and variable bioavailability of lumefantrine, we investigated the possible role of P-glycoprotein (P-gp) in lumefantrine intestinal absorption. Anin situsingle-pass intestinal perfusion study in rats with the P-gp inhibitor verapamil or quinidine and an ATPase assay with human P-gp membranes indicated that lumefantrine is a substrate of P-gp which limits its intestinal absorption. To confirm these findings, anin vivopharmacokinetic study was performed in rats. The oral administration of verapamil (10 mg/kg of body weight) along with lumefantrine caused a significant increase in its bioavailability with a concomitant decrease in clearance. The increase in bioavailability of lumefantrine could be due to inhibition of P-gp and/or cytochrome P450 3A in the intestine/liver by verapamil. However, in a rat intestinal microsomal stability study, lumefantrine was found to be resistant to oxidative metabolism. Further, anin situpermeation study clearly showed a significant role of P-gp in limiting the oral absorption of lumefantrine. Thus, the increase in lumefantrine bioavailability with verapamil is attributed in part to the P-gp-inhibitory ability of verapamil. In conclusion, lumefantrine is a substrate of P-gp, and active efflux by P-gp across the intestine partly contributed to the low/variable bioavailability of lumefantrine.

Assessment of Pharmacokinetic Drug–Drug Interactions in Humans: In Vivo Probe Substrates for Drug Metabolism and Drug Transport Revisited

2019 ◽  
Vol 59 (1) ◽  
pp. 507-536 ◽  
Author(s):  
Uwe Fuhr ◽  
Chih-hsuan Hsin ◽  
Xia Li ◽  
Wafaâ Jabrane ◽  
Fritz Sörgel
Keyword(s):  
Drug Transport ◽  
Quantitative Prediction ◽  
Pharmacokinetic Parameters ◽  
Glycoprotein P ◽  
Therapeutic Drugs ◽  
P Glycoprotein ◽  
Clinical Drug ◽  
Pharmacokinetic Drug

Pharmacokinetic parameters of selective probe substrates are used to quantify the activity of an individual pharmacokinetic process (PKP) and the effect of perpetrator drugs thereon in clinical drug–drug interaction (DDI) studies. For instance, oral caffeine is used to quantify hepatic CYP1A2 activity, and oral dagibatran etexilate for intestinal P-glycoprotein (P-gp) activity. However, no probe substrate depends exclusively on the PKP it is meant to quantify. Lack of selectivity for a given enzyme/transporter and expression of the respective enzyme/transporter at several sites in the human body are the main challenges. Thus, a detailed understanding of the role of individual PKPs for the pharmacokinetics of any probe substrate is essential to allocate the effect of a perpetrator drug to a specific PKP; this is a prerequisite for reliably informed pharmacokinetic models that will allow for the quantitative prediction of perpetrator effects on therapeutic drugs, also in respective patient populations not included in DDI studies.

Role of P-Glycoprotein and Cytochrome P450 3A in Limiting Oral Absorption of Peptides and Peptidomimetics†

1998 ◽  
Vol 87 (11) ◽  
pp. 1322-1330 ◽  
Author(s):  
Vincent J. Wacher ◽  
Jeffrey A. Silverman ◽  
Yuanchao Zhang ◽  
Leslie Z. Benet
Keyword(s):  
Cytochrome P450 ◽  
Oral Absorption ◽  
Cytochrome P450 3A ◽  
P Glycoprotein

scholarly journals A study of intestinal absorption of bicyclol in rats: active efflux transport and metabolism as causes of its poor bioavailability

2008 ◽  
Vol 11 (3) ◽  
pp. 97 ◽  
Author(s):  
Wei Tan ◽  
Hui Chen ◽  
Jinping Hu ◽  
Yan Li
Keyword(s):  
Cell Monolayer ◽  
Intestinal Perfusion ◽  
Efflux Transport ◽  
Glycoprotein P ◽  
Active Efflux ◽  
The Poor ◽  
P Glycoprotein ◽  
Respective Contribution ◽  
Monolayer Model

Purpose.To determine the possible mechanism of poor bioavailability of bicyclol, and clarify the respective contribution of P- glycoprotein (P-gp) and Cytochrome 3A (CYP3A). Methods. Rat in situ single-pass intestinal perfusion and Caco-2 cell monolayer model with selective inhibitors of CYP3A and P-gp were employed. Results. In rat intestinal perfusion, bicyclol (50µM) appearance in mesenteric blood (Pblood) was increased 3, 12, 16-fold by addition of inhibitors of P-gp (LSN335984), CYP3A ( troleandomycin, TAO) or P-gp and CYP3A (Cyclosporin A, CsA), respectively, whereas permeability of midazolam (CYP3A substrate only) was unchanged by LSN335984 and increased 5 and 1-fold by TAO and CsA. In addition, the metabolized fraction of bicyclol was decreased by 9%, 33%, 36% with inhibitor of P-gp, CYP3A, or P-gp and CYP3A. Moreover, the cumulative amount of bicyclol in mesenteric blood was increased at concentration range 10-100µM of bicyclol in perfusate. The ER (Pappba/Pappab) value of bicyclol in Caco-2 monolayer was significantly deceased by LSN335984 and CsA. Conclusion. The poor bioavailability of bicyclol was mostly due to the P-gp mediated efflux and metabolism by CYP3A in intestine, while CYP3A was believed to make more contribution than P-gp.

Pharmacogenetics of Clozapine: In Vivo Role of Cytochrome P450 Isoforms and P-Glycoprotein

2008 ◽  
Vol 41 (05) ◽  
Author(s):  
E Jaquenoud-Sirot ◽  
B Knezevic ◽  
G Perla Morena ◽  
P Baumann ◽  
CB Eap
Keyword(s):  
Cytochrome P450 ◽  
P Glycoprotein ◽  
Cytochrome P450 Isoforms

Comparison of the intestinal absorption and bioavailability of γ-tocotrienol and α-tocopherol: in vitro, in situ and in vivo studies

2012 ◽  
Vol 33 (5) ◽  
pp. 246-256 ◽  
Author(s):  
Bilal S. Abuasal ◽  
Hisham Qosa ◽  
Paul W. Sylvester ◽  
Amal Kaddoumi
Keyword(s):  
Intestinal Absorption ◽  
In Vivo Studies

scholarly journals Upregulations of Clcn3 and P-Gp Provoked by Lens Osmotic Expansion in Rat Galactosemic Cataract

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
Lixia Ji ◽  
Lixia Cheng ◽  
Zhihong Yang
Keyword(s):  
Osmotic Stress ◽  
Early Stage ◽  
Lens Epithelial Cells ◽  
Anterior Capsule ◽  
Glycoprotein P ◽  
Protein Levels ◽  
P Glycoprotein ◽  
Sugar Cataract

Objective.Lens osmotic expansion, provoked by overactivated aldose reductase (AR), is the most essential event of sugar cataract. Chloride channel 3 (Clcn3) is a volume-sensitive channel, mainly participating in the regulation of cell fundamental volume, and P-glycoprotein (P-gp) acts as its modulator. We aim to study whether P-gp and Clcn3 are involved in lens osmotic expansion of galactosemic cataract.Methods and Results.In vitro, lens epithelial cells (LECs) were primarily cultured in gradient galactose medium (10–60 mM), more and more vacuoles appeared in LEC cytoplasm, and mRNA and protein levels of AR, P-gp, and Clcn3 were synchronously upregulated along with the increase of galactose concentration. In vivo, we focused on the early stage of rat galactosemic cataract, amount of vacuoles arose from equatorial area and scattered to the whole anterior capsule of lenses from the 3rd day to the 9th day, and mRNA and protein levels of P-gp and Clcn3 reached the peak around the 9th or 12th day.Conclusion. Galactosemia caused the osmotic stress in lenses; it also markedly leads to the upregulations of AR, P-gp, and Clcn3 in LECs, together resulting in obvious osmotic expansion in vitro and in vivo.

Sign in / Sign up

Export Citation Format

Share Document