Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide

Niemi, Mikko; Tornio, Aleksi; Pasanen, Marja K.; Fredrikson, Hanna; Neuvonen, Pertti J.; Backman, Janne T.

doi:10.1007/s00228-006-0133-z

Cited by 73 publications

(57 citation statements)

References 32 publications

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“…time frame sufficiently small to represent a single time point. Gemfibrozil was considered to be a suitable inhibitor, because clinically used gemfibrozil doses lead to strong, long-lasting mechanism-based inhibition of CYP2C8 Niemi et al, 2003Niemi et al, , 2004aNiemi et al, , 2006Shitara et al, 2004;Jaakkola et al, 2005;Ogilvie et al, 2006;Tornio et al, 2008;Baer et al, 2009), it has no clinically relevant inhibitory effect on CYP3A4, and it has a much shorter half-life than the expected CYP2C8 half-life. A potential problem in our approach was that some degree of competitive OATP1B1 inhibition can occur after gemfibrozil intake (Shitara et al, 2004), as repaglinide is a substrate for this transporter (Niemi et al, 2005;Kalliokoski et al, 2008b).…”

Section: Discussionmentioning

confidence: 99%

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

Backman

Honkalammi²,

Neuvonen³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Gemfibrozil 1-O-␤-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of gemfibrozil treatment using repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.25 mg of repaglinide alone or after different time intervals after a 3-day treatment with 600 mg of gemfibrozil twice daily. The area under the plasma concentration-time curve (AUC) from time 0 to infinity of repaglinide was 7.6-, 2.9-, 1.4-and 1.0-fold compared with the control phase when it was administered 1, 24, 48, or 96 h after the last gemfibrozil dose, respectively (P < 0.001 versus control for 1, 24, and 48 h after gemfibrozil). Thus, a strong CYP2C8 inhibitory effect persisted even after gemfibrozil and gemfibrozil 1-O-␤-glucuronide concentrations had decreased to less than 1% of their maximum (24-h dosing interval). In addition, the metabolite to repaglinide AUC ratios indicated that significant (P < 0.05) inhibition of repaglinide metabolism continued up to 48 h after gemfibrozil administration. Based on the recovery of repaglinide oral clearance, the in vivo turnover half-life of CYP2C8 was estimated to average 22 ؎ 6 h (mean ؎ S.D.). In summary, CYP2C8 activity is recovered gradually during days 1 to 4 after gemfibrozil discontinuation, which should be considered when CYP2C8 substrate dosing is planned. The estimated CYP2C8 half-life will be useful for in vitro-in vivo extrapolations of drug-drug interactions involving induction or mechanism-based inhibition of CYP2C8.

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Section: Discussionmentioning

confidence: 99%

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

Backman

Honkalammi²,

Neuvonen³

et al. 2009

Drug Metab Dispos

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“…Loperamide is an over-the-counter, peripherally-acting, µ-opioid receptor agonist used for the treatment of diarrhea [1]. It undergoes considerable first-pass metabolism, and intestinal absorption is incomplete with poor central nervous system (CNS) penetration related to P-glycoprotein expression limiting abuse potential.…”

Section: Introductionmentioning

confidence: 99%

Conduction Disturbances and Ventricular Arrhythmias Associated with High- Dose Loperamide

Leung

Altshuler²,

Goldenberg³

et al. 2016

J Clinic Toxicol

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Although loperamide has been widely used for the treatment of diarrhea, there is growing popularity over its abuse potential in alleviating opioid-withdrawal symptoms and achieving euphoria. Toxic levels of loperamide have been associated with life-threatening ventricular tachyarrhythmias and cardiac arrest. We report a case of high-dose loperamide ingestion in a patient presenting initially with unstable bradycardia followed by episodes of polymorphic ventricular tachycardia, and an unmasked Brugada ECG pattern. This is the first such report of the Brugada pattern being unmasked on ECG with loperamide ingestion. The patient stabilized with supportive care without the need for inotropic support. We discuss potential mechanisms of toxicity leading to conduction abnormalities and provide a literature review of all published cases of loperamide toxicity to describe proposed treatment options. Recognition of the abuse potential and hazards of this over-the-counter anti-diarrheal therapy will alert the clinician of associated toxidromes and management strategies.

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“…The importance of CYP2C8-mediated drug interactions is increasing continuously, because the list of CYP2C8 substrates, and therefore the list of potential victim drugs of CYP2C8-mediated interactions, is increasing. To date, for example, paclitaxel, cerivastatin, loperamide, rosiglitazone, repaglinide, amiodarone, amodiaquine, and montelukast have been recognized as CYP2C8 substrates (Rahman et al, 1994;Ohyama et al, 2000;Backman et al, 2002;Wang et al, 2002;Niemi et al, 2003a;Kim et al, 2004;Jaakkola et al, 2005;Kajosaari et al, 2005a;Totah and Rettie, 2005;Niemi et al, 2006;Lai et al, 2009;Karonen et al, 2010;Filppula et al, 2011). When developing new therapeutic agents, it is important, among other things, to assess whether their metabolism is dependent on CYP2C8 (Huang et al, 2007(Huang et al, , 2008.…”

Section: Introductionmentioning

confidence: 99%

Dose-Dependent Interaction between Gemfibrozil and Repaglinide in Humans: Strong Inhibition of CYP2C8 with Subtherapeutic Gemfibrozil Doses

Honkalammi¹,

Niemi²,

Neuvonen³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Gemfibrozil 1-O-␤-glucuronide inactivates CYP2C8 irreversibly. We investigated the effect of gemfibrozil dose on CYP2C8 activity in humans using repaglinide as a probe drug. In a randomized, five-phase crossover study, 10 healthy volunteers ingested 0.25 mg of repaglinide 1 h after different doses of gemfibrozil or placebo. Concentrations of plasma repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. A single gemfibrozil dose of 30, 100, 300, and 900 mg increased the area under the concentration-time curve of repaglinide 1.8-, 4.5-, 6.7-, and 8.3-fold (P < 0.001), and its peak concentration 1.4-, 1.7-, 2.1-, and 2.4-fold (P < 0.05), compared with placebo, respectively. Gemfibrozil pharmacokinetics was characterized by a slightly more than doseproportional increase in the area under the curve of gemfibrozil and its glucuronide. The gemfibrozil-repaglinide interaction could be mainly explained by gemfibrozil 1-O-␤-glucuronide concentration-dependent, mechanism-based inhibition of CYP2C8, with a minor contribution by competitive inhibition of organic aniontransporting polypeptide 1B1 at the highest gemfibrozil dose. The findings are consistent with ϳ50% inhibition of CYP2C8 already with a single 30-mg dose of gemfibrozil and >95% inhibition with 900 mg. In clinical drug-drug interaction studies, a single 900-mg dose of gemfibrozil can be used to achieve nearly complete inactivation of CYP2C8.

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Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide

Cited by 73 publications

References 32 publications

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

Conduction Disturbances and Ventricular Arrhythmias Associated with High- Dose Loperamide

Dose-Dependent Interaction between Gemfibrozil and Repaglinide in Humans: Strong Inhibition of CYP2C8 with Subtherapeutic Gemfibrozil Doses

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