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Carrier-mediated intestinal drug abs...

Putnam, Wendy Sue.

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Carrier-mediated intestinal drug absorption: In vitro and in vivo studies.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Carrier-mediated intestinal drug absorption: In vitro and in vivo studies./
Author:	Putnam, Wendy Sue.
Description:	160 p.
Notes:	Adviser: Leslie Z. Benet.
Contained By:	Dissertation Abstracts International63-07B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3058762
ISBN:	0493739742

Carrier-mediated intestinal drug absorption: In vitro and in vivo studies.
Putnam, Wendy Sue.

Carrier-mediated intestinal drug absorption: In vitro and in vivo studies. - 160 p.

Adviser: Leslie Z. Benet.

Thesis (Ph.D.)--University of California, San Francisco, 2002.

In vitro and in vivo studies were conducted to understand and predict the effects of intestinal transporters on the absorption of orally delivered drugs. Bidirectional transport studies were used to determine if fast-growing MDCK cell monolayers could be used as an alternative to traditional 21-day Caco-2 cell monolayers for evaluating carrier-mediated intestinal transport of new drug candidates. Absorptive monocarboxylic acid, large neutral amino acid, bile acid and peptide transporters and an efflux transporter, P-glycoprotein (Pgp), were functionally characterized in these cell lines using six probe substrates. In the presence of a pH gradient, benzoic acid and cephalexin exhibited apparent permeability ratios (apical-to-basolateral permeability/basolateral-to-apical permeability), ranging from 14–25 and 14–71, respectively, in MDCK cells. Benzoic acid absorption was inhibited by valproic acid, while cephalexin absorption was inhibited by glycylsarcosine. Phenylalanine exhibited a much lower apparent permeability ratio of 1.8–2.0 in both MDCK and Caco-2 cells, while taurocholic acid exhibited carrier-mediated absorption only in Caco-2 cells. Both cyclosporine and fexofenadine exhibited Pgp-mediated efflux, which was more sensitive to inhibition in MDCK cells than in Caco-2 cells. These results suggest that MDCK cell monolayers are a useful in vitro intestinal model for evaluating carrier mediated transport by the monocarboxylic acid and peptide transporters and P-glycoprotein, but they are less useful for investigating intestinal bile acid or large neutral amino acid transport. In addition to the in vitro studies, a clinical study was conducted to determine if a genetic variant in the multidrug resistance MDR1 gene encoding P-glycoprotein affected the pharmacokinetics of a Pgp substrate, dicloxacillin, prior to and after rifampin treatment. Healthy volunteers took a 1 g dose of dicloxacillin on the first study day and another dicloxacillin dose on the 11<super>th</super> day of rifampin dosing (600 mg daily). A silent C3435T mutation in exon 26 of the MDR1 gene did not affect the disposition of dicloxacillin. However, rifampin treatment significantly increased the mean absorption time of dicloxacillin, decreased the dicloxacillin C<sub>max</sub> and area under the curve (AUC) and increased the formation clearance of the 5-hydroxymethyl metabolite of dicloxacillin, consistent with upregulation of P-glycoprotein and increased dicloxacillin metabolism.

ISBN: 0493739742Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Carrier-mediated intestinal drug absorption: In vitro and in vivo studies.
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100 1 $a Putnam, Wendy Sue. $3 1256330
245 1 0 $a Carrier-mediated intestinal drug absorption: In vitro and in vivo studies.
300 $a 160 p.
500 $a Adviser: Leslie Z. Benet.
500 $a Source: Dissertation Abstracts International, Volume: 63-07, Section: B, page: 3250.
502 $a Thesis (Ph.D.)--University of California, San Francisco, 2002.
520 $a In vitro and in vivo studies were conducted to understand and predict the effects of intestinal transporters on the absorption of orally delivered drugs. Bidirectional transport studies were used to determine if fast-growing MDCK cell monolayers could be used as an alternative to traditional 21-day Caco-2 cell monolayers for evaluating carrier-mediated intestinal transport of new drug candidates. Absorptive monocarboxylic acid, large neutral amino acid, bile acid and peptide transporters and an efflux transporter, P-glycoprotein (Pgp), were functionally characterized in these cell lines using six probe substrates. In the presence of a pH gradient, benzoic acid and cephalexin exhibited apparent permeability ratios (apical-to-basolateral permeability/basolateral-to-apical permeability), ranging from 14–25 and 14–71, respectively, in MDCK cells. Benzoic acid absorption was inhibited by valproic acid, while cephalexin absorption was inhibited by glycylsarcosine. Phenylalanine exhibited a much lower apparent permeability ratio of 1.8–2.0 in both MDCK and Caco-2 cells, while taurocholic acid exhibited carrier-mediated absorption only in Caco-2 cells. Both cyclosporine and fexofenadine exhibited Pgp-mediated efflux, which was more sensitive to inhibition in MDCK cells than in Caco-2 cells. These results suggest that MDCK cell monolayers are a useful in vitro intestinal model for evaluating carrier mediated transport by the monocarboxylic acid and peptide transporters and P-glycoprotein, but they are less useful for investigating intestinal bile acid or large neutral amino acid transport. In addition to the in vitro studies, a clinical study was conducted to determine if a genetic variant in the multidrug resistance MDR1 gene encoding P-glycoprotein affected the pharmacokinetics of a Pgp substrate, dicloxacillin, prior to and after rifampin treatment. Healthy volunteers took a 1 g dose of dicloxacillin on the first study day and another dicloxacillin dose on the 11<super>th</super> day of rifampin dosing (600 mg daily). A silent C3435T mutation in exon 26 of the MDR1 gene did not affect the disposition of dicloxacillin. However, rifampin treatment significantly increased the mean absorption time of dicloxacillin, decreased the dicloxacillin C<sub>max</sub> and area under the curve (AUC) and increased the formation clearance of the 5-hydroxymethyl metabolite of dicloxacillin, consistent with upregulation of P-glycoprotein and increased dicloxacillin metabolism.
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