Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery

Benet, Leslie Z.; Izumi, Tohru; Zhang, Yuanchao; Silverman, Jeffrey A.; Wacher, Vincent J.

doi:10.1016/s0168-3659(99)00034-6

Cited by 269 publications

(185 citation statements)

References 21 publications

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“…The absorption rate of nevirapine, after the morning dose, was almost sixfold lower when coadministered with rifampicin. Rifampicin has been shown to decrease the rate of absorption of cyclosporine [27]. Further, in the presence of P-glycoprotein (P-gp) inhibitors, the k a of [ 14 C]bepotastine in the small intestine has been shown to increase [28].…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

Elsherbiny

Cohen

Jansson

et al. 2008

Eur J Clin Pharmacol

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

Elsherbiny

Cohen

Jansson

et al. 2008

Eur J Clin Pharmacol

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“…In addition to its expression in multidrug resistance tumor cells, the distribution of P-gp includes the epithelial cells lining the luminal surface of enterocytes in the small intestine, the canalicular surface of heptocytes, the apical surface of epithelial cells of proximal renal tubules, epithelial cells of placenta on the maternal blood flow side, and the luminal surface of capillary endothelial cells comprising the blood-brain barrier (BBB) (Cordon-Cardo et al, 1989;Lieberman et al, 1989;Fardel et al, 1993;Gatmaitan and Arias, 1993;Bendayan et al, 2002). It is becoming increasingly apparent that P-gp plays an important role in the disposition of numerous structurally diverse drugs that are its substrates (Benet et al, 1999). For example, owing to its active efflux, P-gp limits the intestinal absorption of cyclosporine, ivermectin, and paclitaxel after oral dosing (Sparreboom et al, 1997;Kwei et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro

Zhu

Wang

Markowitz

et al. 2006

Neuropsychopharmacol

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Risperidone (RSP) and its major active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the drug transporter P-glycoprotein (P-gp). The goal of this study was to examine the in vitro effects of RSP and PALI on P-gp-mediated transport. The intracellular accumulation of rhodamine123 (Rh123) and doxorubicin (DOX) were examined in LLC-PK1/MDR1 cells to evaluate P-gp inhibition by RSP and PALI. Both compounds significantly increased the intracellular accumulation of Rh123 and DOX in a concentrationdependent manner. The IC 50 values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 mM, respectively, whereas the IC 50 values of PALI were 4100 mM, indicating that PALI is a less potent P-gp inhibitor. Caco-2 and primary cultured rat brain microvessel endothelial cells (RBMECs) were utilized to investigate the possible influence of RSP on intestinal absorption and blood-brain barrier (BBB) transport of coadministered drugs that are P-gp substrates. RSP, 1-50 mM, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC 50 value of 5.87 mM. Following exposure to 10 mM RSP, the apparent permeability coefficient of Rh123 across Caco-2 and RBMECs monolayers was increased to 2.02 and 2.63-fold in the apical to basolateral direction, but decreased to 0.37 and 0.21-fold in the basolateral to apical direction, respectively. These data suggest that RSP and PALI, to a lesser extent, have a potential to influence the pharmacokinetics and hence the pharmacodynamics of coadministered drugs via inhibition of P-gp-mediated transport. However, no human data exist that address this issue. In particular, RSP may interact with its own active metabolite PALI by promoting its brain concentration through inhibiting P-gp-mediated efflux of PALI across endothelial cells of the BBB.

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“…The multidrug efflux pump, P-glycoprotein (P-gp), and cytochrome P450 (CYP) 3A, a major phase I metabolic enzyme in the intestine, play a primary role in limiting the absorption of oral tacrolimus. Intestinal CYP3A and P-gp may act synergistically as a barrier to oral drug absorption (4), and a strong substrate overlap between P-gp and CYP3A has been demonstrated (5). The human multidrug resistance gene (MDR1) encodes for P-gp, and approximately 16 different single nucleotide polymorphisms have been identified within MDR1 (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

Zheng

Webber

Zeevi

et al. 2003

American Journal of Transplantation

248

174

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Tacrolimus is a substrate for P-glycoprotein (P-gp) and cytochrome (CYP) P4503A. P-gp is encoded by the multiple drug resistance gene MDR1 and CYP3A is the major enzyme responsible for tacrolimus metabolism. Both MDR1 and CYP3A5 genes have multiple single nucleotide polymorphisms. The objective of this study was to evaluate whether the MDR1 exon21 and exon26 polymorphisms and the CYP3A5 polymorphism are associated with tacrolimus disposition in pediatric heart transplant patients. At 3, 6 and 12 months post transplantation, a significant difference in tacrolimus blood level per dose/kg/day was found between the CYP3A5 *1/*3 (CYP3A5 expressor) vs. *3/*3 (nonexpressor) genotypes with the *1/*3 patients requiring a larger tacrolimus dose to maintain the same blood concentration. There were no significant differences in tacrolimus blood level per dose/kg/day between MDR1 exon21 G2677T and exon 26 C3435T at 3 months, but both were found to have a significant association with tacrolimus blood level per dose/kg/day at 6 and 12 months. We conclude that specific genotypes of MDR1 and CYP3A5 in pediatric heart transplant patients require larger tacrolimus doses to maintain their tacrolimus blood concentration, and that this information could be used prospectively to manage patient's immunosuppressive therapy.

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Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery

Cited by 269 publications

References 21 publications

Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro

Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

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