A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug–Drug Interaction Studies

Hanke, Nina; Türk, Denise; Selzer, Dominik; Wiebe, Sabrina; Fernandez, Eric; Stopfer, Peter; Nock, Valerie; Lehr, Thorsten

doi:10.3390/pharmaceutics12060556

Cited by 13 publications

(11 citation statements)

References 52 publications

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“…However, adding norverapamil can resolve the FNs even if using 4.5 μM as the inhibition potency for verapamil. Norverapamil was also incorporated in a physiologically‐based pharmacokinetic (PBPK) model used to predict the effect of verapamil on several substrates including digoxin 38 …”

Section: In Vitro–in Vivo Extrapolation Of Systemic P‐gp Inhibitionmentioning

confidence: 99%

Clinical Relevance of Hepatic and Renal P‐gp/BCRP Inhibition of Drugs: An International Transporter Consortium Perspective

Taskar

Yang

Patel

et al. 2022

Clin Pharma and Therapeutics

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The role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in drug-drug interactions (DDIs) and limiting drug absorption as well as restricting the brain penetration of drugs with certain physicochemical properties is well known. P-gp/BCRP inhibition by drugs in the gut has been reported to increase the systemic exposure to substrate drugs. A previous International Transporter Consortium (ITC) perspective discussed the feasibility of P-gp/BCRP inhibition at the blood-brain barrier and its implications. This ITC perspective elaborates and discusses specifically the hepatic and renal P-gp/BCRP (referred as systemic) inhibition of drugs and whether there is any consequence for substrate drug disposition. This perspective summarizes the clinical evidence-based recommendations regarding systemic P-gp and BCRP inhibition of drugs with a focus on biliary and active renal excretion pathways. Approaches to assess the clinical relevance of systemic P-gp and BCRP inhibition in the liver and kidneys included (i) curation of DDIs involving intravenously administered substrates or inhibitors; (ii) in vitro-to-in vivo extrapolation of P-gp-mediated DDIs at the systemic level; and (iii) curation of drugs with information available about the contribution of biliary excretion and related DDIs. Based on the totality of evidence reported to date, this perspective supports limited clinical DDI risk upon P-gp or BCRP inhibition in the liver or kidneys.

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Section: In Vitro–in Vivo Extrapolation Of Systemic P‐gp Inhibitionmentioning

confidence: 99%

Clinical Relevance of Hepatic and Renal P‐gp/BCRP Inhibition of Drugs: An International Transporter Consortium Perspective

Taskar

Yang

Patel

et al. 2022

Clin Pharma and Therapeutics

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“… 68 It is also worth noting that verapamil is an inhibitor as well as a substrate for both CYP3A4 and P‐gp. 69 …”

Section: Renal Impairmentmentioning

confidence: 99%

Drug–Drug Interactions in People Living With HIV at Risk of Hepatic and Renal Impairment: Current Status and Future Perspectives

Cottura

Kinvig

Grañana-Castillo

et al. 2022

The Journal of Clinical Pharma

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Despite the advancement of antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV), drug-drug interactions (DDIs) remain a relevant clinical issue for people living with HIV receiving ART. Antiretroviral (ARV) drugs can be victims and perpetrators of DDIs, and a detailed investigation during drug discovery and development is required to determine whether dose adjustments are necessary or coadministrations are contraindicated. Maintaining therapeutic ARV plasma concentrations is essential for successful ART, and changes resulting from potential DDIs could lead to toxicity, treatment failure, or the emergence of ARV-resistant HIV. The challenges surrounding DDI management are complex in special populations of people living with HIV,and often lack evidence-based guidance as a result of their underrepresentation in clinical investigations.Specifically, the prevalence of hepatic and renal impairment in people living with HIV are between five and 10 times greater than in people who are HIV-negative, with each condition constituting approximately 15% of non-AIDS-related mortality. Therapeutic strategies tend to revolve around the treatment of risk factors that lead to hepatic and renal impairment, such as hepatitis C, hepatitis B, hypertension, hyperlipidemia, and diabetes. These strategies result in a diverse range of potential DDIs with ART. The purpose of this review was 2-fold. First, to summarize current pharmacokinetic DDIs and their mechanisms between ARVs and co-medications used for the prevention and treatment of hepatic and renal impairment in people living with HIV. Second, to identify existing knowledge gaps surrounding DDIs related to these special populations and suggest areas and techniques to focus upon in future research efforts.

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“…Karaciğerde ilk geçiş etkisine uğraması, S-verapamil biyoyararlanımındaki düşüşün nedenidir. 26,27 Verapamilin kararlı duruma eriştiğindeki dağılım hacmi R izomerinin 2,74 iken S izomerininki 6,42'dir. 23 Başka bir kardiyovasküler sistem ilacı örneği olarak, bir rasemat olan varfarinin yapısında bulunan R-varfarin, plazma proteinine S-varfarine göre daha düşük oranda bağlanır, daha yüksek dağılım hacmine sahiptir.…”

Section: Temel Tanımlar Ve Kavramlarunclassified

The Concept of Chirality and its Association with Drug Safety: Traditional Review

BAHAR¹,

SONMEZ²,

VIZDIKLAR³

et al. 2022

J Lit Pharm Sci

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A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug–Drug Interaction Studies

Cited by 13 publications

References 52 publications

Clinical Relevance of Hepatic and Renal P‐gp/BCRP Inhibition of Drugs: An International Transporter Consortium Perspective

Clinical Relevance of Hepatic and Renal P‐gp/BCRP Inhibition of Drugs: An International Transporter Consortium Perspective

Drug–Drug Interactions in People Living With HIV at Risk of Hepatic and Renal Impairment: Current Status and Future Perspectives

The Concept of Chirality and its Association with Drug Safety: Traditional Review

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