Active metabolites formed during hepatic first-pass: simulations featuring their contribution to the overall effect in altered liver clearance and drug-drug interactions

Benzodiazepines have been touted as safer alternatives to their barbiturate predecessor since their arrival on the market in 1960. Their proposed improved safety is based on their reported reduced drug interactions, lower abuse potential, and decreased respiratory depression. Benzodiazepines bind to the GABAA receptor and positively modulate GABAergic transmission and hyperpolarization of neuronal membranes. Individual agents are utilized differently depending on their varying degrees of hypnotic, anxiolytic, antiepileptic, muscle relaxant, and amnestic properties. Benzodiazepines are frequently classified by their half-life (t½), a key pharmacokinetic parameter that dictates the agents’ ability to precipitate dangerous withdrawals. The majority of benzodiazepines undergo phase I hepatic metabolism via cytochrome p450 that introduce the potential for drug interactions. Following hepatic metabolism, almost all agents within this drug class have active metabolites that have extended half-lives beyond that of the parent drug that prolong the duration of activity. Urine drug screens are an essential component of medication monitoring and require a foundational understanding of the parent drug, its metabolites, and what the available immunoassay is designed to detect. A similar drug class that is frequently grouped with benzodiazepines are Z-drugs. These agents were developed in attempt to create a sleep aid that lacked the undesirable qualities of benzos with an improved safety profile. Z-drugs share the common characteristic of being short-acting in nature and are proposed to cause less disruption in the normal sleep cycle than benzodiazepines.

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Ethanol and drug interactions

Therapeutische Umschau ◽

10.1024/0040-5930.57.4.220 ◽

2000 ◽

Vol 57 (4) ◽

pp. 220-226 ◽

Cited By ~ 2

Author(s):

Oneta

Keyword(s):

Drug Interactions ◽

Zytochrom P450 ◽

First Pass

Der Alkoholstoffwechsel findet vor allem in der Leber statt. Dabei spielt beim Alkoholabstinenten die Alkoholdehydrogenase (ADH) die wichtigste Rolle. Beim chronischen Trinker hingegen gewinnt der Alkoholabbauweg über das mikrosomale Äthanol-oxidierende System (MEOS), insbesondere über das Zytochrom P450 2E1, infolge Induktion ganz entscheidend an Bedeutung. Es kann in dieser Situation vier- bis zehnmal mehr Alkohol metabolisieren. Da das mikrosomale Enzymsystem neben Alkohol auch diverse Medikamente verstoffwechselt, wird es zum Spielball für klinisch bedeutsame Alkohol-Medikamenten Interaktionen. Die klinisch relevanten Interaktionen werden abgehandelt. Im weiteren wird auf die Bedeutung des sogenannten First-pass Stoffwechsels im Magen eingegangen. Der einzige Weg zur Verhinderung schwerwiegender Alkohol-Medikamenten Interaktionen ist die Verbreitung deren Kenntnis sowohl unter Ärzte als auch Patienten.

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Potential role of intestinal first-pass metabolism in the prediction of drug–drug interactions

Expert Opinion on Drug Metabolism & Toxicology ◽

10.1517/17425255.4.7.909 ◽

2008 ◽

Vol 4 (7) ◽

pp. 909-922 ◽

Cited By ~ 77

Author(s):

Aleksandra Galetin ◽

Michael Gertz ◽

J Brian Houston

Keyword(s):

Drug Interactions ◽

Potential Role ◽

First Pass Metabolism ◽

First Pass ◽

Pass Metabolism

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An update on the potential role of intestinal first-pass metabolism for the prediction of drug–drug interactions: the role of PBPK modeling

Expert Opinion on Drug Metabolism & Toxicology ◽

10.1080/17425255.2018.1482277 ◽

2018 ◽

Vol 14 (6) ◽

pp. 625-634 ◽

Cited By ~ 2

Author(s):

Saeed Alqahtani ◽

Ishfaq Bukhari ◽

Ahmed Albassam ◽

Maha Alenazi

Keyword(s):

Drug Interactions ◽

Potential Role ◽

Pbpk Modeling ◽

First Pass Metabolism ◽

First Pass ◽

Pass Metabolism

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Lack of Indinavir Effects on Methadone Disposition Despite Inhibition of Hepatic and Intestinal Cytochrome P4503A (CYP3A)

Anesthesiology ◽

10.1097/aln.0b013e3182423478 ◽

2012 ◽

Vol 116 (2) ◽

pp. 432-447 ◽

Cited By ~ 29

Author(s):

Evan D. Kharasch ◽

Pamela Sheffels Bedynek ◽

Christine Hoffer ◽

Alysa Walker ◽

Dale Whittington

Keyword(s):

Plasma Concentration ◽

Drug Interactions ◽

Plasma Concentrations ◽

Antiretroviral Drugs ◽

Cyp3a Activity ◽

Oral Clearance ◽

Hepatic Extraction ◽

Time Curve ◽

Apparent Oral Clearance ◽

First Pass

Background Methadone disposition and pharmacodynamics are highly susceptible to interactions with antiretroviral drugs. Methadone clearance and drug interactions have been attributed to cytochrome P4503A4 (CYP3A4), but actual mechanisms are unknown. Drug interactions can be clinically and mechanistically informative. This investigation assessed effects of the protease inhibitor indinavir on methadone pharmacokinetics and pharmacodynamics, hepatic and intestinal CYP3A4/5 activity (using alfentanil), and intestinal transporter activity (using fexofenadine). Methods Twelve healthy volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone. This was repeated after 2 weeks of indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by miosis. Results Indinavir significantly inhibited hepatic and first-pass CYP3A activity. Intravenous alfentanil systemic clearance and hepatic extraction were reduced to 40-50% of control, apparent oral clearance to 30% of control, and intestinal extraction decreased by half, indicating 50% and 70% inhibition of hepatic and first-pass CYP3A activity. Indinavir increased fexofenadine area under the plasma concentration-time curve 3-fold, suggesting significant P-glycoprotein inhibition. Indinavir had no significant effects on methadone plasma concentrations, methadone N-demethylation, systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Methadone plasma concentration-effect relationships were unaffected by indinavir. Conclusions Despite significant inhibition of hepatic and intestinal CYP3A activity, indinavir had no effect on methadone N-demethylation and clearance, suggesting little or no role for CYP3A in clinical disposition of single-dose methadone. Inhibition of gastrointestinal transporter activity had no influence of methadone bioavailability.

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