Oral absorption of the HIV protease inhibitors: a current update

Williams, Gregory C.; Sinko, Patrick J.

doi:10.1016/s0169-409x(99)00027-7

Cited by 126 publications

(90 citation statements)

References 75 publications

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“…As illustrated in Figure 6, the low affinity of digoxin for the OATP2B1 isoform was confirmed with no effect on E3S accumulation. In contrast, the less specific and/or more potent (Williams and Sinko, 1999;Hoetelmans R, 2003;Perry et al, 2005;Swainston Harrison and Scott, 2005;Marin-Niebla et al, 2007;Ruane et al, 2007;Chandwani and Shuter, 2008) **: due to solubility limitations, nelfinavir could only be tested up to a concentration of 20 !M …”

Section: Discussionmentioning

confidence: 99%

Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1

et al. 2010

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The effects of human immunodeficiency virus (HIV) protease inhibitors (PI) on the accumulation of the fluorescent bile salt analogue cholyl-glycylamido-fluorescein (CGamF) were determined in organic anion transporting polypeptide (OATP)-1B1 and -1B3-expressing Chinese hamster ovary (CHO) cells. In addition, interaction studies in Caco-2 monolayers, known only to express the OATP2B1 isoform, were conducted using the established OATP substrate estrone 3-sulfate (E3S), since no CGamF accumulation was observed in Caco-2 monolayers. CGamF appeared an excellent substrate for the OATP1B subfamily, with net accumulation clearance values of 7.8 and 142 microl min(-1) mg(-1) protein in OATP1B1 and OATP1B3-transfected cells, respectively. K(i)-values reflecting inhibition of CGamF accumulation by HIV PI correlated well between OATP1B1 and OATP1B3-expressing cells. Lopinavir was the most potent inhibitor (K(i) = 0.5-1.4 microM) of OATP1B-mediated CGamF accumulation compared with atazanavir, darunavir, ritonavir, and saquinavir (K(i) between 1.4 and 3.3 microM). Inhibitory profiles towards OATP2B1-mediated E3S accumulation were different with only indinavir, saquinavir, and ritonavir showing substantial effects. In conclusion, OATP1B3 appears to be a major transport mechanism mediating sodium-independent CGamF accumulation in human liver, and CGamF could be used as a probe substrate for in vitro drug interaction studies. The remarkably potent inhibition of OATP1B1 by lopinavir may explain some clinically relevant drug interactions between lopinavir and OATP1B substrates such as fexofenadine.

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Section: Discussionmentioning

confidence: 99%

Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1

et al. 2010

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“…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. Potential interaction between efflux transporters in the gut and CYP3A4 metabolizing enzymes may be a source of variation associated with LVR absorption and distribution (Williams and Sinko, 1999). In human, CYP3A4 is the principal enzyme involved in the hepatic and intestinal drug metabolism, and there is a striking overlap of substrate specificites among CYP3A4, P-gp and MRPs.…”

Section: Introductionmentioning

confidence: 99%

“…Because these efflux transporters are oriented in the secretory (i.e., out of the organ or tissue) direction, high efflux will lead to lower net absorption for LVR. Subtherapeutic concentrations of PIs in the sanctuary sites like brain, testes and bone-marrow may cause persistence of viral infections leading to drug resistance (Williams and Sinko, 1999). Therefore, the purpose of this study is to assess the affinity of LVR for the efflux transporters using a well-defined system consisting of polarized non-human (canine) MDCKII cells, singly transfected with human MDR1, human MRP1/MRP2 complementary DNA (cDNA) or murine Bcrp1 cDNA and also to delineate quantitatively whether efflux limits permeation of LVR across intestinal and BBB absorptive 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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“…3,5,8,19) Therefore, elimination of these drugs from the body through the intestine at least depends on the synergetic effect of CYP3A and P-gp function. In addition, the contribution of the P-gp efflux system into the intestine after oral administration of a drug is essentially given by the sum of transport of the drug from the bloodstream to the intestine and secretion of the drug just after being absorbed into the epithelial cells.…”

Section: Discussionmentioning

confidence: 99%