Interaction between Ketoconazole and Almotriptan in Healthy Volunteers

Fleishaker, Joseph C.; Herman, Beth D.; Carel, Barbara J.; Azie, Nkechi

doi:10.1177/0091270003252242

Cited by 27 publications

(17 citation statements)

References 11 publications

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“…0.5 mg/kg nifedipine to dogs showed 1.83-fold increase in AUC, and 1.73-and 1.2-fold decreases in the CL and V dss , respectively (Kuroha et al, 2002). Similarly, coadministration of 12.5 mg of almotriptan, a selective 5-HT 1B/1D agonist, and 400 mg of KTZ to healthy volunteers generated a 44% decrease in the V z /F of almotriptan (Fleishaker et al, 2003). In subjects given KTZ (200 mg/day for 3 consecutive days orally) with docetaxel (10 mg/m 2 ), an 18.7% decrease in docetaxel V dss was reported (Engels et al, 2004).…”

Section: Discussionmentioning

confidence: 93%

Determination of the Enzyme(s) Involved in the Metabolism of Amiodarone in Liver and Intestine of Rat: The Contribution of Cytochrome P450 3a Isoforms

Shayeganpour¹,

El‐Kadi²,

Brocks³

2005

Drug Metab Dispos

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ABSTRACT:In humans, cytochrome P450 3A (CYP3A4) is a major enzyme involved in the metabolism of amiodarone (AM) to its major metabolite, desethylamiodarone (DEA). In rat, a commonly used animal model, metabolism of AM has not been well studied. To determine whether DEA is formed by CYP3A isoenzymes in the rat, microsomal protein was harvested from liver and intestine of male Sprague-Dawley rats. The metabolism of AM in each tissue was assessed utilizing chemical and immunological inhibitors. Ketoconazole, a presumed inhibitor of CYP3A1/2, significantly inhibited formation of DEA by hepatic and intestinal microsomes. However, based on the DEA formation kinetics in both microsomal preparations, it appeared that more than one cytochrome P450 enzyme was involved in the process. Coincubation of AM with microsomes and anti-CYP3A2 confirmed the role of CYP3A2 in the metabolism of AM in liver. DEA was also formed by rat recombinant CYP1A1 and CYP3A1, and was inhibited by ketoconazole; hence the participation of these enzymes in the intestinal DEA formation is likely. However, anti-CYP2B1/2 or -CYP1A2 antibodies had no effect on DEA formation. In rats given oral or intravenous AM, oral ketoconazole caused significant increases in area under the concentration versus time curve (AUC) of oral and i.v. treated rats and greater than 50% decreases in the total body clearance and V dss of i.v. treated rats. Although low to undetectable concentrations of DEA were a limitation for determination of AUC of DEA in vivo, it was confirmed that ketoconazole could cause a significant increase in AM concentrations in rat.Amiodarone (AM) is an iodinated class III antiarrhythmic benzofuran derivative with extensive clinical usage (Trivier et al., 1993;Soyama et al., 2002) in the treatment of life-threatening ventricular and supraventricular arrhythmias (Naccarelli et al., 2000). AM undergoes extensive hepatic biotransformation (Trivier et al., 1993;Soyama et al., 2002). Among the five pathways involved in the metabolism of AM (N-deethylation, hydroxylation, O-dealkylation, deiodination, and glucuronidation), N-dealkylation is most important in humans (Trivier et al., 1993;Soyama et al., 2002). The dealkylated metabolite, desethylamiodarone (DEA) shares some of the pharmacological and toxicological properties of AM. For instance, some of the electrocardiographic changes observed after long-term therapy with AM might be related to DEA (Kharidia and Eddington, 1996;Kodama et al., 1999). In addition, both AM and DEA inhibit the intracellular conversion of thyroxine to triiodothyronine. This inhibition may be related to some cardiotoxic effects of AM such as bradycardia and reduced myocardial oxygen consumption, and may explain the hypothyroid-like condition observed after chronic administration of AM (Hudig et al., 1994;Kodama et al., 1999).AM possesses a very large pharmacokinetic volume of distribution (V d ) and extensive tissue distribution, and, in turn, a long terminal half-life (t 1/2 ) in rat and human plasma (Pollak et al., 2000;Shaye...

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Section: Discussionmentioning

confidence: 93%

Determination of the Enzyme(s) Involved in the Metabolism of Amiodarone in Liver and Intestine of Rat: The Contribution of Cytochrome P450 3a Isoforms

Shayeganpour¹,

El‐Kadi²,

Brocks³

2005

Drug Metab Dispos

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“…Use a lower dose of the triptan or not to use it within 72 h by a strong CYP3A4 inhibitor; monitor patients for increased triptan adverse reactions [125,126] Eletriptan/ergot derivatives Increased risk of ergotism Inhibition of ergot derivatives metabolism (CYP 3A4-mediated)…”

Section: Risk Of Serotoninergic Syndromementioning

confidence: 99%

Medication overuse and chronic migraine: a critical review according to clinical pharmacology

Ferrari

Baraldi

Sternieri

2015

Expert Opinion on Drug Metabolism & Toxicology

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In spite of progress in migraine treatment, the prevalence of chronic headaches and MOH has not changed in the course of time. Today, a large number of migraine patients have turned to numerous expert physicians and experienced all sorts of prophylactic treatments without decisive benefits. Their condition seems to have crystallized even more as chronic and intractable. This means that to prevent chronification and MOH, we need more effective drugs and better strategies to use them. In particular, we must detect disease biomarkers and predictive factors for drug response that allow for personalized treatment when migraine is still episodic and make analgesic overuse pointless.

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“…Inhibition of CYP3A4 is a major mechanism of undesirable drug-drug interaction, [49] rendering CYP3A4 an important antitarget. We retrieved a total of 3150 informative SAR pairs from the Aureus database based on MMPs to generate informative SAR pairs.…”

Section: Cyp3a4 Inhibitionmentioning

confidence: 99%

Identification and Application of Antitarget Activity Hotspots to Guide Compound Optimization

Heßler

Matter

Schmidt

et al. 2011

Molecular Informatics

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The optimization of a lead structure to a development candidate often requires removal of undesirable antitarget activities. To this end, we have developed an approach to extract antitarget activity hotspots from larger databases and to transfer this knowledge onto novel chemical series. These antitarget activity hotspots will be captured as pairs of informative molecules, which are chemically closely related, but differ significantly in biological activity. We illustrate the application of antitarget activity hotspots as informative compound pairs for the optimization of side effects in lead structures for relevant antitargets in pharmaceutical research. The use for prospective design requires establishing a structural link between known antitarget hotspot pairs and a new lead structure: we employ 3D-based similarity comparison for this task. The entire workflow serves as idea generator in early optimization. The feasibility of this approach is demonstrated in several optimization problems related to hERG inhibition, and CYP3A4 inhibition. Several structural examples demonstrate the ability of the 3D-shape searching to identify related scaffolds and the usefulness of the antitarget hotspot information to guide optimization by modulating the undesirable antitarget activity. Such a concept based on the analysis of local similarities and the transfer to 3D-related series is especially promising in those cases, where the construction of antitarget QSAR models fails to detect local SAR trends for guiding the next optimization cycle.

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Interaction between Ketoconazole and Almotriptan in Healthy Volunteers

Cited by 27 publications

References 11 publications

Determination of the Enzyme(s) Involved in the Metabolism of Amiodarone in Liver and Intestine of Rat: The Contribution of Cytochrome P450 3a Isoforms

Determination of the Enzyme(s) Involved in the Metabolism of Amiodarone in Liver and Intestine of Rat: The Contribution of Cytochrome P450 3a Isoforms

Medication overuse and chronic migraine: a critical review according to clinical pharmacology

Identification and Application of Antitarget Activity Hotspots to Guide Compound Optimization

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