N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine (CP-100,356) as a “chemical knock-out equivalent” to assess the impact of efflux transporters on oral drug absorption in the rat

Kalgutkar, Amit S.; Frederick, Kosea S.; Chupka, Jonathan; Feng, Bo; Kempshall, Sarah; Mireles, Rochelle J.; Fenner, Katherine; Troutman, Matthew D.

doi:10.1002/jps.21756

Cited by 28 publications

(17 citation statements)

References 59 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibition of the P-gp transporter results in the accumulation of calcein within the cell and a corresponding increase in cellular fluorescence (Tiberghien and Loor, 1996). A proprietary Pfizer compound, N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine (CP100356), has been validated as a potent P-gp inhibitor with maximal inhibition at 5 M (Kalgutkar et al, 2009). The inhibition of P-gp with 5 M CP100356 was used as a 100% inhibitory control, which was then used to compare calcein AM inhibition by ivermectin and spinosad.…”

Section: Interaction Of Ivermectin and Spinosad In Dogsmentioning

confidence: 99%

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

et al. 2011

View full text Add to dashboard Cite

ABSTRACT:Neurological side effects consistent with ivermectin toxicity have been observed in dogs when high doses of the common heartworm prevention agent ivermectin are coadministered with spinosad, an oral flea prevention agent. Based on numerous reports implicating the role of the ATP-binding cassette drug transporter P-glycoprotein (P-gp) in ivermectin efflux in dogs, an in vivo study was conducted to determine whether ivermectin toxicity results from a pharmacokinetic interaction with spinosad. Beagle dogs were randomized to three groups treated orally in parallel: Treatment group 1 (T01) received ivermectin (60 g/kg), treatment group 2 (T02) received spinosad (30 mg/kg), and treatment group 3 (T03) received both ivermectin and spinosad. Whereas spinosad pharmacokinetics were unchanged in the presence of ivermectin, ivermectin plasma pharmacokinetics revealed a statistically significant increase in the area under the curve (3.6-fold over the control) when ivermectin was coadministered with spinosad. The majority of the interaction is proposed to result from inhibition of intestinal and/or hepatic P-gp-mediated secretory pathways of ivermectin. Furthermore, in vitro Transwell experiments with a human multidrug resistance 1-transfected Madin-Darby canine kidney II cell line showed polarized efflux at concentrations <2 M, indicating that spinosad is a high-affinity substrate of P-gp. In addition, spinosad was a strong inhibitor of the P-gp transport of digoxin, calcein acetoxymethyl ester (IC 50 ‫؍‬ 3.2 M), and ivermectin (IC 50 ‫؍‬ 2.3 M). The findings suggest that spinosad, acting as a P-gp inhibitor, increases the risk of ivermectin neurotoxicity by inhibiting secretion of ivermectin to increase systemic drug levels and by inhibiting P-gp at the blood-brain barrier.

show abstract

Section: Interaction Of Ivermectin and Spinosad In Dogsmentioning

confidence: 99%

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

et al. 2011

View full text Add to dashboard Cite

show abstract

“…To determine the effect of P-gp inhibition on the interplay, we employed CP100356 [N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine] and PSC833 [valspodar, 6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-L-valine-cyclosporin A] as selective P-gp inhibitors because of their high selectivity ratio for P-gp to CYP3A (Wandel et al, 1999;Kalgutkar et al, 2009). We included verapamil and ketoconazole, well-established inhibitors of both P-gp and CYP3A with different ratios of inhibitory potency (Wandel et al, 1999), as dual inhibitors to further explore the consequences of the interplay-based DDIs.…”

Section: Introductionmentioning

confidence: 99%

The Consequence of Drug-Drug Interactions Influencing the Interplay between P-Glycoprotein and Cytochrome P450 3a: An Ex Vivo Study with Rat Precision-Cut Intestinal Slices

Graaf

Siissalo

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) are differentially expressed along the intestine and work coordinately to reduce the intracellular concentration of xenobiotics and the absorption of orally taken drugs. Drug-drug interactions (DDIs) based on P-gp/CYP3A interplay are of clinical importance and require preclinical investigation. We investigated the P-gp/Cyp3a interplay and related DDIs with different P-gp inhibitors in the various regions of the rat intestine ex vivo using precision-cut intestinal slices (PCIS) with quinidine (Qi), a dual substrate of P-gp and Cyp3a, as the probe. The results showed that P-gp efflux was the main factor limiting the intracellular Qi content at concentrations below 5 mM, whereas both efflux and metabolism were saturated at [Qi] > 50 mM. The selective P-gp inhibitors CP100356 [N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine] and PSC833 [valspodar, 6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-Lvaline-cyclosporin A] enhanced the Qi accumulation in slices in line with the different P-gp expression in the intestinal regions and, as a result, also enhanced metabolism in the jejunum and ileum. Dual inhibitors of both P-gp and Cyp3a (verapamil and ketoconazole) increased the concentration of Qi in the jejunum and ileum, but less 3-hydroxy-quinidine was produced due to inhibition of Cyp3a. The results indicate that the P-gp/Cyp3a interplay depends on the concentration of the drug and on the intestinal region under study. Furthermore, due to the P-gp/Cyp3a interplay, DDIs can lead to remarkable changes in the intracellular concentration of both the parent drug and the metabolite, which varies among the intestinal regions and depends on the selectivity of the inhibitors, with potentially important implications for disposition and toxicity of drugs and their metabolites.

show abstract

“…However, the lack of specific inhibitors presents challenges to the assessment of Bcrp contribution to PK in rats (Kalgutkar et al, 2009). Abcg2 knockout homozygous rats were developed recently by using targeted, CompoZr ZFN technology in Sprague-Dawley embryos (www.sageresearchmodels.com).…”

Section: Introductionmentioning

confidence: 99%

Deletion ofAbcg2Has Differential Effects on Excretion and Pharmacokinetics of Probe Substrates in Rats

Huang

Tchaparian

et al. 2012

J Pharmacol Exp Ther

View full text Add to dashboard Cite

This study was designed to characterize breast cancer resistance protein (Bcrp) knockout Abcg2(Ϫ/Ϫ) rats and assess the effect of ATP-binding cassette subfamily G member 2 (Abcg2) deletion on the excretion and pharmacokinetic properties of probe substrates. Deletion of the target gene in the Abcg2(Ϫ/Ϫ) rats was confirmed, whereas gene expression was unaffected for most of the other transporters and metabolizing enzymes. Biliary excretion of nitrofurantoin, sulfasalazine, and compound A [2-(5-methoxy-2-((2-methyl-1,3-benzothiazol-6-yl)amino)-4-pyridinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one] accounted for 1.5, 48, and 48% of the dose in the Abcg2(ϩ/ϩ) rats, respectively, whereas it was decreased by 70 to 90% in the Abcg2(Ϫ/Ϫ) rats. Urinary excretion of nitrofurantoin, a significant elimination pathway, was unaffected in the Abcg2(Ϫ/Ϫ) rats, whereas renal clearance of sulfasalazine, a minor elimination pathway, was reduced by Ͼ90%. Urinary excretion of compound A was minimal. Systemic clearance in the Abcg2(Ϫ/Ϫ) rats decreased 22, 43 (p Ͻ 0.05), and 57%, respectively, for nitrofurantoin, sulfasalazine, and compound A administered at 1 mg/kg and 27% for compound A administered at 5 mg/kg. Oral absorption of nitrofurantoin, a compound with high aqueous solubility and good permeability, was not limited by Bcrp. In contrast, the absence of Bcrp led to a 33-and 11-fold increase in oral exposure of sulfasalazine and compound A, respectively. These data show that Bcrp plays a crucial role in biliary excretion of these probe substrates and has differential effects on systemic clearance and oral absorption in rats depending on clearance mechanisms and compound properties. The Abcg2(Ϫ/Ϫ) rat is a useful model for understanding the role of Bcrp in elimination and oral absorption.

show abstract

N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine (CP-100,356) as a “chemical knock-out equivalent” to assess the impact of efflux transporters on oral drug absorption in the rat

Cited by 28 publications

References 59 publications

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

The Consequence of Drug-Drug Interactions Influencing the Interplay between P-Glycoprotein and Cytochrome P450 3a: An Ex Vivo Study with Rat Precision-Cut Intestinal Slices

Deletion ofAbcg2Has Differential Effects on Excretion and Pharmacokinetics of Probe Substrates in Rats

Contact Info

Product

Resources

About