Effect of Chronic Hepatitis C on the Activity of the Membrane Transporters P‐gp and OATP1B1/BCRP on Patients With Different Stages of Hepatic Fibrosis

Pippa, Leandro Francisco; Vieira, Carolina Pinto; Caris, Juciene Aparecida; Rocha, Adriana; Marques, Maria Paula; Garcia, Camile Prates; Rezende, Rosamar Eulira Fontes; Lanchote, Vera Lúcia

doi:10.1002/cpt.2908

Cited by 3 publications

(1 citation statement)

References 47 publications

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“…However, these studies have not mimicked the physiological inflammatory conditions in humans, making it difficult to translate the findings to changes in the in vivo pharmacokinetics (PK) of drugs in humans. Studies from this research group have reported that systemic inflammation resulting from rheumatoid arthritis, systemic lupus erythematosus, visceral leishmaniasis, and chronic hepatitis C alters the activity of CYP enzymes and hepatic/intestinal drug transporters [4][5][6][7][8]. However, to date, have been no studies on the impact of inflammation on the in vivo activities of the renal transporters, especially during pregnancy.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Inflammation on the In Vivo Activity of the Renal Transporters OAT1/3 in Pregnant Women Diagnosed with Acute Pyelonephritis

Benzi,

Melli,

Duarte

et al. 2023

Pharmaceutics

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Inflammation can regulate hepatic drug metabolism enzymes and transporters. The impact of inflammation on renal drug transporters remains to be elucidated. We aimed to quantify the effect of inflammation (caused by acute pyelonephritis) on the in vivo activity of renal OAT1/3, using the probe drug furosemide. Pregnant women (second or third trimester) received a single oral dose of furosemide 40 mg during acute pyelonephritis (Phase 1; n = 7) and after its resolution (Phase 2; n = 7; by treatment with intravenous cefuroxime 750 mg TID for 3–7 days), separated by 10 to 14 days. The IL-6, IFN-γ, TNF-α, MCP-1, and C-reactive protein plasma concentrations were higher in Phase I vs. Phase II. The pregnant women had a lower geometric mean [CV%] furosemide CLsecretion (3.9 [43.4] vs. 6.7 [43.8] L/h) and formation clearance to the glucuronide (1.1 [85.9] vs. 2.3 [64.1] L/h) in Phase 1 vs. Phase 2. Inflammation reduced the in vivo activity of renal OAT1/3 (mediating furosemide CLsecretion) and UGT1A9/1A1 (mediating the formation of furosemide glucuronide) by approximately 40% and 54%, respectively, presumably by elevating the plasma cytokine concentrations. The dosing regimens of narrow therapeutic window OAT drug substrates may need to be adjusted during inflammatory conditions.

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Section: Introductionmentioning

confidence: 99%

The Impact of Inflammation on the In Vivo Activity of the Renal Transporters OAT1/3 in Pregnant Women Diagnosed with Acute Pyelonephritis

Benzi,

Melli,

Duarte

et al. 2023

Pharmaceutics

Self Cite

View full text Add to dashboard Cite

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Impact of Inflammation on the In Vivo Activity of the Renal Transporters OAT1/3 in Pregnant Women Diagnosed with Acute Pyelonephritis

Benzi,

Melli,

Duarte

et al. 2023

Preprint

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Inflammation can regulate hepatic drug metabolism enzymes and transporters. The impact of inflammation on renal drug transporters remains to be elucidated. We aimed to quantify the effect of inflammation (caused by acute pyelonephritis) on the in vivo activity of renal OAT1/3, using the probe drug furosemide. Pregnant women (2nd or 3rd trimester) received a single oral dose of furosemide 40 mg during acute pyelonephritis (Phase 1; n = 7) and after its resolution (Phase 2; n = 7; by treatment with intravenous cefuroxime 750 mg TID for 3-7 days), separated by 10 to 14 days. IL-6, IFN-γ, TNF-α, MCP-1, and C-reactive protein plasma concentrations were higher in Phase I vs Phase II. The pregnant women had a lower geometric mean [CV%] furosemide CLsecretion (3.9 [43.4] vs 6.7 [43.8] L/h) and formation clearance to the glucuronide (1.1 [85.9] vs 2.3 [64.1] L/h) in Phase 1 vs. Phase 2. Inflammation reduced the in vivo activity of renal OAT1/3 (mediating furosemide CLsecretion) and UGT1A9/1A1 (mediating the formation of furosemide glucuronide) by approximately 40% and 54%, respectively, presumably by elevating plasma cytokine concentrations. The dosing regimens of narrow therapeutic window OAT drug substrates may need to be adjusted during inflammatory conditions.

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The Role of CYPs and Transporters in the Biotransformation and Transport of the Anti-hepatitis C Antiviral Agents Asunaprevir, Daclatasvir, and Beclabuvir: Impact of Liver Disease, Race and Drug-drug Interactions on Safety and Efficacy

Murray

2024

CDM

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Asunaprevir, daclatasvir, and beclabuvir are direct-acting antiviral agents used in the treatment of patients infected with hepatitis C genotype 1b. This article reviews the biotransformation and disposition of these drugs in relation to the safety and efficacy of therapy. CYP3A4 and 3A5 catalyze the oxidative biotransformation of the drugs, while P-glycoprotein mediates their efflux from tissues. Asunaprevir is also a substrate for the influx transporters OATP1B1 and OATP2B1 and the efflux transporter MRP2, while beclabuvir is also a substrate for the efflux transporter BCRP. Liver disease decreases the expression of CYPs and transporters that mediate drug metabolism and disposition. Serum asunaprevir concentrations, but not those of daclatasvir or beclabuvir, are increased in patients with severe liver disease, which may produce toxicity. Pharmacogenomic variation in CYPs and transporters also has the potential to disrupt therapy with asunaprevir, daclatasvir and beclabuvir; some variants are more prevalent in certain racial groups. Pharmacokinetic drug-drug interactions, especially where asunaprevir, daclatasvir, and beclabuvir are victim drugs, are mediated by coadministered rifampicin, ketoconazole and ritonavir, and are attributable to inhibition and/or induction of CYPs and transporters. Conversely, there is also evidence that asunaprevir, daclatasvir and beclabuvir are perpetrators of drug interactions with coadministered rosuvastatin and dextromethorphan. Together, liver disease, pharmacogenomic variation and drug-drug interactions may disrupt

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Effect of Chronic Hepatitis C on the Activity of the Membrane Transporters P‐gp and OATP1B1/BCRP on Patients With Different Stages of Hepatic Fibrosis

Cited by 3 publications

References 47 publications

The Impact of Inflammation on the In Vivo Activity of the Renal Transporters OAT1/3 in Pregnant Women Diagnosed with Acute Pyelonephritis

The Impact of Inflammation on the In Vivo Activity of the Renal Transporters OAT1/3 in Pregnant Women Diagnosed with Acute Pyelonephritis

Impact of Inflammation on the In Vivo Activity of the Renal Transporters OAT1/3 in Pregnant Women Diagnosed with Acute Pyelonephritis

The Role of CYPs and Transporters in the Biotransformation and Transport of the Anti-hepatitis C Antiviral Agents Asunaprevir, Daclatasvir, and Beclabuvir: Impact of Liver Disease, Race and Drug-drug Interactions on Safety and Efficacy

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