Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐glycoprotein: Implications for drug delivery and activity in cancer chemotherapy

Wacher, Vincent J.; Wu, Chengqing; Benet, Leslie Z.

doi:10.1002/mc.2940130302

Cited by 795 publications

(469 citation statements)

References 81 publications

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“…A further complication is the overlapping substrate specificities of CYP3A4 and permeability glycoprotein (P-gp). 16 Interindividual variability of CYP450 enzyme activity is influenced by the frequent presence of allelic singlenucleotide polymorphisms (SNPs), some of which result in reduction or ablation of their metabolic activity. CYP2C19 has over 20 polymorphisms that result in truncated or inactive enzyme 17 and one that causes enhanced activity.…”

Section: Introductionmentioning

confidence: 99%

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Ashbee

Gilleece

2011

Bone Marrow Transplant

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Section: Introductionmentioning

confidence: 99%

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Ashbee

Gilleece

2011

Bone Marrow Transplant

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“…In vitro investigations with human liver microsomes have shown that cytochrome P450 3A plays a predominant role in the metabolism of LVR. High first pass metabolism can also occur due to intestinal efflux which can lead to increased exposure time to metabolizing enzymes (Wacher et al, 1995;Wacher et al, 2001;Katragadda et al, 2005). We have hypothesized that the low oral bioavailability of LVR and possibly limited brain penetration could be in part due to efflux of LVR by several efflux pumps such as Pglycoprotein (P-gp), multidrug-resistance related proteins (MRPs) and breast cancer resistance protein (BCRP) present on intestinal epithelial and blood capillary endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Agarwal

Pal

Mitra

2007

International Journal of Pharmaceutics

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Polarized epithelial non-human (canine) cell lines stably transfected with human or murine complementary DNA (cDNA) encoding for various efflux transporters (P-gp/MDR1, MRP1, MRP2, and Bcrp1) were used to study transepithelial transport of Lopinavir (LVR) and compare results with the MDCKII-Wild type cells. These transmembrane proteins cause multidrug resistance by decreasing the total intracellular accumulation of drugs. Lopinavir efflux was directional and was completely inhibited by MK-571, a selective MRP family inhibitor in the MDCKII-MRP2 cell line. Similarly, LVR efflux was also inhibited by P-gp inhibitors P-gp 4008 and GF120918 in the MDCKII-MDR1 cell line. The efflux ratios (Efflux rate/ Influx rate) of LVR in the absence of any efflux inhibitors in the MDCK-Wild type, MDCKII-MDR1, MDCKII-MRP1 and MDCKII-MRP2 cell monolayers were 1.32, 4.91, 1.26 and 2.89 respectively. The MDCKII-MDR1 and MDCKII-MRP2 cells have significantly increased LVR efflux ratio relative to the parental cells due to the apically directed transport by MDR1 and MRP2 respectively. The efflux ratios in MRP2 and MDR1 transfected cell lines were close to unity in the presence of MK-571 and P-gp 4008 respectively; indicating that LVR efflux by MRP2 and P-gp was completely inhibited by their selective inhibitors. MDCKII-MRP1 cells did not exhibit a significant reduction in the LVR efflux relative to the parental cells, indicating that LVR is not a good substrate for MRP1. Transport studies across MDCKII-Bcrp1 cells indicated that LVR is not transported by Bcrp1 and is not a substrate for this efflux protein. In conclusion, this study presents direct evidence that LVR is effluxed by both P-gp and MRP2 which may contribute to its poor oral bioavailability and limited penetration into the CNS. KeywordsMDCKII-MDR1; MDCKII-MRP2; MDCKII-MRP1; MDCKII-Bcrp1; MDCKII-WT; Pglycoprotein (P-gp); multidrug resistance protein (MRP); breast cancer resistance protein (BCRP); Lopinavir (LVR); uptake; transport; permeability; efflux ratio (ER)

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“…In fact, some investigators consider the two proteins to act in a coordinated and synergistic fashion within some tissues (eg, gastrointestinal epithelium, hepatocytes) to limit absorption or promote elimination of a large number of molecules. [20][21][22] The cyclosporine-mediated increase in methylprednisolone plasma concentration produced a comparable increase in methylprednisolone concentration in muscle (Figure 3). Since muscle does not express p-glycoprotein, and therefore does not actively exclude methylprednisolone, one would expect methylprednisolone concentrations in muscle to parallel those in plasma, which is what was found.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporine-A-mediated inhibition of p-glycoprotein increases methylprednisolone entry into the central nervous system

Bernards

2005

Spinal Cord

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Study design: Prospective, randomized, pharmacokinetic study. Objective: To determine if cyclosporine-A-mediated inhibition of p-glycoprotein would increase methylprednisolone entry into the central nervous system thereby permitting a reduction in the systemic methylprednisolone dose. Setting: Department of Anesthesiology, University of Washington, Seattle, USA. Methods: Microdialysis probes were used to obtain cerebrospinal fluid and gluteal muscle extracellular fluid samples for measurement of methylprednisolone concentration in pigs. At time zero, a methylprednisolone bolus was given and an infusion started. At 210 min, after reaching a stable methylprednisolone concentration, a cyclosporine-A bolus was given (either 10 or 30 mg/kg) and microdialysis samples collected until 420 min. Plasma samples were collected at 10, 30 min and then every 30 min until the study's end. Results: Cyclosporine-A bolus produced a dose-dependant increase in methylprednisolone concentration in plasma, muscle and cerebrospinal fluid. Importantly, the magnitude of the increase in cerebrospinal fluid was significantly greater than the increase in plasma and muscle. Conclusions: The relatively greater increase in cerebrospinal fluid concentrations of methylprednisolone is consistent with increased penetration of the blood-brain barrier secondary to cyclosporine-mediated p-glycoprotein inhibition. Theoretically, increased methylprednisolone entry into the central nervous system should allow a reduction in the systemic methylprednisolone dose and a consequent decrease in glucocorticoid-mediated side effects.

show abstract

Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐glycoprotein: Implications for drug delivery and activity in cancer chemotherapy

Cited by 795 publications

References 81 publications

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Cyclosporine-A-mediated inhibition of p-glycoprotein increases methylprednisolone entry into the central nervous system

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