Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We used renal proximal tubules from a teleost fish (killifish; Fundulus heteroclitus), fluorescent substrates and confocal microscopy to study the interactions between human immunodeficiency virus protease inhibitors and drug-transporting ATPases. Both saquinavir and ritonavir inhibited luminal accumulation of a fluorescent cyclosporin A derivative (a substrate for P-glycoprotein) and of fluorescein methotrexate [a substrate for multidrug resistance-associated protein 2 (Mrp2)]. Of the two protease inhibitors, ritonavir was the more potent inhibitor of transport by a factor of at least 20. Ritonavir was at least as good an inhibitor of P-glycoprotein- and Mrp2-mediated transport as cyclosporin A and leukotriene C4, respectively. Inhibition of P-glycoprotein- and Mrp2-mediated transport was not due to toxicity or impaired metabolism, because neither saquinavir nor ritonavir inhibited transport of fluorescein on the renal organic anion system. Experiments with a fluorescent saquinavir derivative showed strong secretion into the tubular lumen that was inhibited by verapamil, leukotriene C4, saquinavir, and ritonavir. Together, the data demonstrate that saquinavir, and especially ritonavir, are potent inhibitors of P-glycoprotein- and Mrp2-mediated transport. The experiments with the fluorescent saquinavir derivative suggest that these protease inhibitors may also be substrates for both P-glycoprotein and Mrp2.
...
PMID:Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. 1041 58

This study investigated fexofenadine (FXD) transport and the inhibition of FXD transport in Caco-2 cell monolayer transwells, using rhodamine 123 (RH123) transport as a positive control. FXD transport from the basolateral (B) to apical (A) compartment was fivefold higher than A to B transport. FXD transport was linear with respect to time (up to 270 min) and concentration (up to 300 microm). Similar results were seen with the positive control RH123. Ritonavir (100 PM) and verapamil (100 microm) reduced transport of FXD and RH123 by more than 80%, whereas transport was not inhibited by 100 m indomethacin or 2 mM probenecid. This suggests predominantly P-glycoprotein (P-gp)-mediated transport as opposed to transport by multidrug resistance protein. In concentration-response experiments, FXD transport was inhibited by verapamil and ritonavir with IC50 values of 6.5 microm and 5.4 microm, respectively. Results from this in vitro study demonstrate differential transport of FXD across Caco-2 cell monolayers and inhibition of FXD transport by established P-gp inhibitors. Thefindings support the use of FXD as an index or probe compound to reflect P-gp activity in vivo.
...
PMID:Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir. 1241 27

Anti-human immunodeficiency virus (HIV) drug penetration into the brain and cerebrospinal fluid (CSF) is necessary to tackle HIV within the CNS. This study examines movement of [(3)H]ritonavir across the guinea pig blood-brain and blood-CSF barriers and accumulation within the brain, CSF, and choroid plexus. Ritonavir is a protease inhibitor, used in combination therapy (often as a pharmacoenhancer) to treat HIV. Drug interactions at brain barrier efflux systems may influence the CNS penetration of anti-viral drugs, thus the influence of additional protease inhibitors, nucleoside reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors on [(3)H]ritonavir CNS distribution was explored. Additionally, the involvement of transporters on [(3)H]ritonavir passage across the brain barriers was assessed. Results from in situ brain perfusions and capillary depletion analysis demonstrated that [(3)H]ritonavir uptake into the guinea pig brain was considerable (6.6 +/- 0.7 ml/100 g at 30 min, vascular space corrected), although a proportion of drug remained trapped in the cerebral capillaries and did not reach the brain parenchyma. CSF uptake was more limited (2.2 +/- 0.4 ml/100 g at 30 min), but choroid plexus uptake was abundant (176.7 +/- 46.3 ml/100 g at 30 min). [(3)H]Ritonavir brain and CSF uptake was unaffected by neither inhibitors of organic anion transport (probenecid and digoxin) or P-glycoprotein (progesterone), nor by any additional anti-HIV drugs, indicating that brain barrier efflux systems do not significantly limit brain or CSF [(3)H]ritonavir accumulation in this model. [(3)H]Ritonavir uptake into the perfused choroid plexus was significantly reduced by nevirapine and abacavir, additional perfusion studies, and isolated incubated choroid plexus experiments were carried out in an attempt to further characterize the transporter involved.
...
PMID:The distribution of the HIV protease inhibitor, ritonavir, to the brain, cerebrospinal fluid, and choroid plexuses of the guinea pig. 1463 41

Ritonavir is a large, lipophilic molecule that is practically insoluble in aqueous media and exhibits an exceedingly slow intrinsic dissolution rate. Although it has favorable lipophilicity, in vitro permeability studies have shown that ritonavir is a substrate of P-glycoprotein. Thus, the oral absorption of ritonavir could be limited by both dissolution and permeability, thereby making it a Class IV compound in the Biopharmaceutics Classification System. Because formulations rarely exert direct influence on local intestinal permeability, the effect of enhanced dissolution rate on oral absorption was explored. More specifically, poly(ethylene glycol) (PEG)-amorphous ritonavir solid dispersions were prepared with different drug loadings, and the in vitro and in vivo performances of the dispersions were evaluated. In vitro dissolution was conducted in 0.1N HCl with a USP Apparatus I. A crossover design was used to evaluate the oral bioavailability of amorphous dispersions relative to crystalline drug in beagle dogs. Intrinsic dissolution measurements of the two solid phases indicated a 10-fold improvement in intrinsic dissolution rate for amorphous ritonavir compared with the crystalline counterpart. In vitro dissolution of ritonavir depended on the solid phase as well as drug loading of the dispersion. In vivo study results indicate that amorphous solid dispersions containing 10-30% drug exhibited significant increases in area under the curve of concentration versus time (AUC) and maximum concentration (C(max)) over crystalline drug. For example, 10% amorphous dispersion exhibited increases of 22- and 13.7-fold in AUC and C(max), respectively. However, both in vitro dissolution and bioavailability decreased with increasing drug load, which led to the construction of a multiple Level C in vitro-in vivo relationship for this Class IV compound. The established relationship between in vitro dissolution and in vivo absorption can help guide formulation development.
...
PMID:Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. 1476 95

Breast cancer resistance protein (BCRP) is a recently discovered ATP-binding cassette drug transporter. Hence, the full spectrum of therapeutic agents that interact with BCRP remains to be elucidated. Because human immunodeficiency virus protease inhibitors (HPIs) are well known P-glycoprotein (P-gp) substrates, and there is an overlap in substrate specificity between P-gp and BCRP, this study was performed to investigate whether HPIs are substrates and/or inhibitors of BCRP. First, the effect of HPIs on BCRP efflux activity in human embryonic kidney (HEK) cells stably expressing wild-type BCRP (482R) and its two mutants (482T and 482G) was studied by measuring intracellular mitoxantrone fluorescence using flow cytometry. We found that ritonavir, saquinavir, and nelfinavir were effective inhibitors of wild-type BCRP (482R) with IC50 values of 19.5 +/- 0.8 microM, 19.5 +/- 7.6 microM, and 12.5 +/- 4.1 microM, respectively. Ritonavir, saquinavir, and nelfinavir inhibited 482T and 482G with IC50 values that were approximately 2 times greater than that for 482R. Indinavir and amprenavir had no significant inhibition on BCRP activity. Direct efflux of radiolabeled HPIs in HEK cells was measured to determine whether the HPIs are substrates of BCRP. None of the HPIs were found to be transported by BCRP. Together, ritonavir, saquinavir, nelfinavir, indinavir, and amprenavir are not substrates for BCRP. However, ritonavir, saquinavir, and nelfinavir are effective inhibitors of the transporter. These results suggest that BCRP may play an important role in drug-drug interactions involving coadministration of the HPIs with drugs that are substrates of the transporter.
...
PMID:HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). 1500 2

Our objective was to examine the influence of ritonavir on P-glycoprotein (P-gp) activity in humans by characterizing the effect of ritonavir on the pharmacokinetics of the P-gp substrate digoxin in individuals with known MDR1 genotypes. Healthy volunteers received a single dose of digoxin 0.4 mg orally before and after 14 days of ritonavir 200 mg twice daily. After each digoxin dose blood and urine were collected over 72 hours and analyzed for digoxin. Digoxin pharmacokinetic parameter values were determined using noncompartmental methods. MDR1 genotypes at positions 3435 and 2677 in exons 26 and 21, respectively, were determined using PCR-RFLP analysis. Ritonavir increased the digoxin AUC(0-72) from 26.20 +/- 8.67 to 31.96 +/- 11.24 ng x h/mL (P = 0.03) and the AUC(0-8) from 6.25 +/- 1.8 to 8.04 +/- 2.22 ng x h/mL (P = 0.02) in 12 subjects. Digoxin oral clearance decreased from 149 +/- 101 mL/h x kg to 105 +/- 57 mL/h x kg (P = 0.04). Other digoxin pharmacokinetic parameter values, including renal clearance, were unaffected by ritonavir. Overall, 75% (9/12) of subjects had higher concentrations of digoxin after ritonavir administration. The majority of subjects were heterozygous at position 3435 (C/T) (6 subjects) and position 2677 (G/T,A) (7 subjects); although data are limited, the effect of ritonavir on digoxin pharmacokinetics appears to occur across all tested MDR1 genotypes. Concomitant low-dose ritonavir reduced the nonrenal clearance of digoxin, thereby increasing its systemic availability. The most likely mechanism for this interaction is ritonavir-associated inhibition of P-gp. Thus, ritonavir can alter the pharmacokinetics of coadministered medications that are P-gp substrates.
...
PMID:Ritonavir decreases the nonrenal clearance of digoxin in healthy volunteers with known MDR1 genotypes. 1516 36

In view of the very important role played by ritonavir in the prevention of maternal-fetal HIV-vertical transmission, the aim of this experimental study was to evaluate its possible effects on several important obstetric parameters. Ritonavir was administered daily to three groups of pregnant rats (E1 = 20 mg/kg; E2 = 60 mg/kg; E3 = 180 mg/kg; n = 10 in every group) from 'zero' up to the 20th day of pregnancy. Controls (n = 10) were injected with the drug vehicle (propyleneglycol) in the same schedule. We evaluated the effects on fetal and maternal weight gain, placental weight, number of implantations and resorptions, malformations, fertility rate, and maternal and fetal death rates. Body weight gain of the E3 group was significantly lower than that of the other groups, most likely due to a toxic effect of the highest dose of ritonavir. Ritonavir did not affect the number of implantations. Group E3 had five resorptions and some reduction in fertility. The mortality rate was significantly affected by ritonavir (2/10 maternal deaths in E2 and 4/10 in E3). On the other hand, no alterations were observed in the fetuses, a finding which could be due at least in part to the protective action of placental P-glycoprotein.
...
PMID:Effect of chronic ritonavir administration on pregnant rats and their fetuses. 1549 Oct 71

Ritonavir (RTV) is well known as an inhibitor of many drugs that are metabolized by cytochrome P450 (CYP) 3A or fluxed via P-glycoprotein (Pgp), although it is also reported that RTV is a potent inducer for them. In this study, to elucidate these contradictory phenomena, functional changes of CYP3A or Pgp during chronic administration of RTV were examined in rats. After pretreatment with RTV for indicated days (day 3-day 14), rats were used in the experiments. The area under the plasma drug concentration vs. time curve (AUC(0-infinity)) after oral administration of RTV (20 mg/kg) to these rats showed an RTV-treatment period-dependent decrease, and the mean AUC(0-infinity) of RTV in Day 14 rats decreased significantly by 57% as compared to the control. The AUC(0-infinity) after intravenous (i.v.) administration of RTV to Day 3 and Day 5 rats increased significantly by 28% and 22%, respectively, while there were no significant changes in the AUC(0-infinity) in Day 7 and Day 14 rats as compared to the control. As for i.v. administration of erythromycin (EM) or midazolam (MDZ) to RTV-treated rats, the AUC(0-infinity)in Day 3 and Day 5 rats increased significantly as compared to the control, while in Day 7 rats and rifampicin-treated rats, the AUC(0-infinity) of EM decreased significantly by 82% and 42%, respectively, as compared to the control. For MDZ, there were no significant changes in the AUC(0-infinity) in Day 7 or Day 14 rats. After i.v. administration of rhodamine123 (Rho123), the excretion clearances from blood circulation to the intestinal lumen and the biliary excretion clearances in Day 14 rats increased markedly by 2.2-fold and 2.6-fold as compared to the control. It has been confirmed that RTV is not only a potent inhibitor but also a potent inducer of CYP3A, and that RTV is a potent inducer of intestinal Pgp. This property of RTV is responsible for regulating the oral bioavailability of drugs that are mediated by CYP3A and Pgp.
...
PMID:Effect of chronic administration of ritonavir on function of cytochrome P450 3A and P-glycoprotein in rats. 1563 77

The objective of this study is to investigate whether transporter-targeted prodrug derivatization of quinidine, a model P-glycoprotein (P-gp) substrate, can circumvent P-gp-mediated efflux. The L-valine ester of quinidine (val-quinidine) was synthesized in our laboratory. Uptake and transport studies were carried out using the MDCKII-MDRI cell line at 37 degrees C for 10 min and 3 h, respectively. [3H]Ritonavir and cyclosporine were also used as model P-gp substrates to delineate the kinetics of translocation of val-quinidine across the MDCKII-MDRI cell monolayer. The rate of uptake of [3H]ritonavir by MDCKII-MDRI cells exhibited a 2-fold increase in the presence of 75 microM quinidine, but 75 microM val-quinidine did not demonstrate any effect on [3H]ritonavir uptake. The rate of transport of quinidine from the basolateral to the apical membrane [(18.3 +/- 1.25) x 10(-6) cm s(-1)] and from the apical to the basolateral membrane [(6.5 +/- 0.66) x 10(-6) cm s(-1)] exhibited a 3-fold difference. However, transport of val-quinidine from the apical to the basolateral membrane [(5.13 +/- 0.49) x 10(-6) cm s(-1)] and from the basolateral to the apical membrane [(6.17 +/- 1.28) x 10(-6) cm s(-1)] did not demonstrate any statistically significant difference. Moreover, cyclosporine, a potent P-gp substrate and/or inhibitor, did not alter the transport kinetics of val-quinidine. The rates of uptake of [3H]Gly-Sar and various amino acid model substrates were reduced in the presence of 200 microM val-quinidine. Results from this study clearly indicate that prodrug derivatization of quinidine into val-quinidine can overcome P-gp-mediated efflux. Val-quinidine once bound to a peptide or amino acid transporter is probably not recognized and cannot be accessed by the P-gp efflux pump. Transporter-targeted prodrug derivatization seems to be a viable strategy for overcoming P-gp-mediated efflux.
...
PMID:Circumventing P-glycoprotein-mediated cellular efflux of quinidine by prodrug derivatization. 1598 88

Extended treatment with human immunodeficiency virus (HIV) protease inhibitors (HPIs) is standard in HIV/AIDS therapy. While these drugs have helped decrease the overall incidence of AIDS defining illnesses, the relative prevalence of HIV/AIDS dementia has increased. HPIs may cause induction of blood-brain barrier (BBB) drug transporters (P-glycoprotein; P-gp) and thereby limit entry of HPIs into brain tissue, increasing the probability that the brain could become an HIV sanctuary site. Using bovine brain microvessel endothelial cells (BMEC) as an in-vitro model of the BBB, the potential for the HIV protease inhibitor ritonavir to cause induction of P-gp activity and expression was examined. BMEC were isolated from fresh cow brain by enzymatic digest and density centrifugation. Primary culture BMEC were co-incubated with ritonavir or vehicle control for 120 h. Quantitative drug accumulation of rhodamine 123 (Rh123) and fluorescence microscopy were used as measures of P-gp activity. P-gp expression was assessed using quantitative Western blotting. Ritonavir decreased Rh123 cell accumulation and increased P-gp immunoreactive protein in a concentration-dependent manner. Fluorescent microscopy mirrored Rh123 quantitative studies. In BMEC pretreated with 30 microM ritonavir, Rh123 accumulation was decreased 40% and immunoreactive P-gp protein increased 2-fold. Collectively, a strong correlation between decreased Rh123 BMEC accumulation and increased P-gp immunoreactive protein was observed (Spearman r2 = 0.77, P < 0.0001). Thus extended exposure of BMEC to ritonavir caused a concentration-dependent increase in P-gp activity and expression. Similar findings may occur at the clinical level with prolonged HIV protease inhibitor use, giving insight into the central nervous system as an HIV sanctuary site and eventual development of HIV dementia.
...
PMID:Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells. 1763 89


1 2 3 Next >>

---