Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes

Kim, Kyoung Ah; Chung, Jae Hyun; Jung, Dong Hae; Park, Ji Young

doi:10.1007/s00228-004-0815-3

Cited by 70 publications

(61 citation statements)

References 28 publications

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“…It plays an important role in the metabolism of endogenous substances, e.g., arachidonic acid (Rifkind et al, 1995;Ohyama et al, 2000), as well as many drugs, including repaglinide (Bidstrup et al, 2003;Kajosaari et al, 2005a), pioglitazone (Jaakkola et al, 2006), rosiglitazone (Baldwin et al, 1999), loperamide (Kim et al, 2004), amiodarone (Ohyama et al, 2000), cerivastatin (Wang et al, 2002), and paclitaxel (Rahman et al, 1994). Thus, factors affecting CYP2C8 activity may have potentially important effects on drug efficacy and patient safety.…”

mentioning

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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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 undergoes significant first pass metabolism by cytochrome CYP3A4 [7]. High concomitant doses of famotidine may inhibit CYP3A4 (this effect has been demonstrated for other histamine-2 receptor antagonistsparticularly cimetidine) [8][9][10].…”

Section: Discussionmentioning

confidence: 93%

Ventricular Tachycardia Triggered by Loperamide and Famotidine Abuse

Larsen

McMunn

Ahmad

et al. 2017

Journal of the American College of Cardiology

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A 32-year-old male developed recurrent ventricular tachycardia after taking mega doses of loperamide and famotidine in order to experience an opiate-like euphoric effect. He was taking up to 200 mg of loperamide and multiple doses of famotidine each day. He developed palpitations and syncope. Electrocardiography demonstrated ventricular tachycardia and QT interval prolongation (corrected QT interval was 597 ms). He was diagnosed with loperamide-induced QT prolongation resulting in incessant ventricular tachycardia. Loperamide was discontinued, and he was treated with electrolyte replacement, supportive care, and monitoring. After 5 days, his electrocardiogram (ECG) normalized and he had no more ventricular tachycardia. A Naranjo assessment score of 8 was obtained, indicating a probable relationship between QT prolongation and his use of loperamide. Large doses of loperamide can cause QT interval prolongation and lifethreatening arrhythmias. These effects may be accentuated when histamine-2 receptor blockers are also abused. Key PointsLoperamide toxicity can cause lethal cardiac arrhythmias.Co-administration of histamine-2 antagonists may increase the opioid-like euphoric effect of loperamide and increase the risk of cardiotoxicity.Multiple cardiac ion channels may be affected by loperamide overdose.

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“…A previous study reported that loperamide is metabolized to N-demethylated loperamide mainly by CYP3A4 in human liver microsomes 23) and that the metabolism is affected by CYP3A inhibition. 24,25) In contrast, because it is not clear whether loperamide inhibits CYP3A enzyme, our study was designed to focus on loperamide as a CYP3A inhibitor.…”

Section: Discussionmentioning

confidence: 98%

Inhibitory Effects of Gastrointestinal Drugs on CYP Activities in Human Liver Microsomes

Iwase

Nishimura

Kurata

et al. 2017

Biological & Pharmaceutical Bulletin

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OTC drugs have an important role in self-medication. However, the pharmacokinetic properties of some OTC drugs have not been fully investigated and reports concerning their drug interactions are insufficient. Several gastrointestinal drugs are available as OTC drugs. Because of their pharmacological properties, these drugs are often used concomitantly with other drugs. Therefore, it is important to predict the possible drug interactions among these drugs. In the current study, we investigated the inhibitory effects of five gastrointestinal drugs, namely loperamide, oxethazaine, papaverine, pirenzepine, and trimebutine, on CYP activities in human liver microsomes. Furthermore, we calculated the ratio of the intrinsic clearance of each CYP substrate in the presence or absence of the gastrointestinal drugs. The possibility of drug interactions in vivo was predicted by cut-off criteria. CYP3A4 activity was markedly inhibited by trimebutine, papaverine, and oxethazaine. Their inhibitory properties were competitive and the K i values were 6.56, 12.8, and 3.08 µM, respectively. Alternative R values of CYP3A4 exceeded the cut-off level. These results suggested that drug interactions mediated by CYP3A4 may occur during treatment with these gastrointestinal drugs, necessitating the confirmation of the clinical significance of these drug interactions to prevent unexpected adverse effects. Key words gastrointestinal drug; OTC drug; drug interaction; CYPIn recent years, people have become increasingly interested in their own health due to a rapidly aging society and/or the increase of lifestyle-related diseases. As a result, the concept of self-care, which includes self-medication, has attracted popular attention. Self-medication is defined as the selection and use of medicines by individuals to treat self-recognized illnesses or symptoms. 1) Self-medication includes the use of OTC drugs under the advice of healthcare professionals such as pharmacists.2) Therefore, OTC drugs play an important role in self-medication. OTC drugs are considered relatively safer than ethical drugs. However, many OTC drugs, especially those developed in the distant past, have not had their pharmacokinetic properties sufficiently studied. They may be safe to use alone; however, there is no evidence to suggest their safety when combined with other drugs.Many drug interactions affect specific metabolic processes, especially those mediated by CYP. CYP-mediated drug interactions are roughly classified into enzyme inhibition and enzyme induction. Most are based on enzyme inhibition, with many documented clinically significant cases. Therefore, it is important to examine whether OTC drugs have inhibitory effects on CYP activity.A recent study reported that diphenhydramine interacted with metoprolol via CYP2D6 inhibition.3) Diphenhydramine potently inhibited metoprolol α-hydroxylation in vitro. Moreover, a clinical study found that diphenhydramine decreased metoprolol metabolic clearance 2.5-fold in CYP2D6 extensive metabolizers.4) Diphenhydramine, a fir...

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Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes

Cited by 70 publications

References 28 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

Ventricular Tachycardia Triggered by Loperamide and Famotidine Abuse

Inhibitory Effects of Gastrointestinal Drugs on CYP Activities in Human Liver Microsomes

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