Comparative effect of famotidine and cimetidine on the pharmacokinetics of theophylline in normal volunteers.

Lin, J H; Chremos, Athanassios N.; Chiou, R.; Yeh, Kuang C.; Williams, Roger L.

doi:10.1111/j.1365-2125.1987.tb03228.x

Cited by 22 publications

(10 citation statements)

References 12 publications

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“…While apixaban is metabolized primarily by CYP3A4 and is a substrate for P-glycoprotein and breast cancer resistance protein, famotidine is minimally metabolized, is primarily eliminated unchanged in urine, and is a substrate for P-glycoprotein 20. Famotidine has minimal potential for CYP450-mediated drug–drug interactions 22–24. However, it is an inhibitor of hOCT uptake transporters 25.…”

Section: Discussionmentioning

confidence: 99%

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Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor

Upreti

Wang²,

Byon³

et al. 2013

CPAA

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BackgroundApixaban is an oral, selective, direct factor Xa inhibitor approved for thromboprophylaxis after orthopedic surgery and stroke prevention in patients with atrial fibrillation, and under development for treatment of venous thromboembolism. This study investigated the effect of a gastric acid suppressant, famotidine (a histamine H2-receptor antagonist), on the pharmacokinetics of apixaban in healthy subjects.MethodsThis two-period, two-treatment crossover study randomized 18 healthy subjects to receive a single oral dose of apixaban 10 mg with and without a single oral dose of famotidine 40 mg administered 3 hours before dosing with apixaban. Plasma apixaban concentrations were measured up to 60 hours post-dose and pharmacokinetic parameters were calculated.ResultsFamotidine did not affect maximum apixaban plasma concentration (Cmax) or area under the plasma concentration-time curve from zero to infinite time (AUC∞). Point estimates for ratios of geometric means with and without famotidine were close to unity for Cmax (0.978) and AUC∞ (1.007), and 90% confidence intervals were entirely contained within the 80%–125% no-effect interval. Administration of apixaban alone and with famotidine was well tolerated.ConclusionFamotidine does not affect the pharmacokinetics of apixaban, consistent with the physicochemical properties of apixaban (lack of an ionizable group and pH-independent solubility). Apixaban pharmacokinetics would not be affected by an increase in gastrointestinal pH due to underlying conditions (eg, achlorhydria), or by gastrointestinal pH-mediated effects of other histamine H2-receptor antagonists, antacids, or proton pump inhibitors. Given that famotidine is also an inhibitor of the human organic cation transporter (hOCT), these results indicate that apixaban pharmacokinetics are not influenced by hOCT uptake transporter inhibitors. Overall, these results support that apixaban can be administered without regard to coadministration of gastric acid modifiers.

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Section: Discussionmentioning

confidence: 99%

“…Famotidine is minimally metabolized and primarily eliminated unchanged in the urine 21. Famotidine has minimal potential for CYP-mediated drug–drug interactions 22–24…”

Section: Introductionmentioning

confidence: 99%

Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor

Upreti

Wang²,

Byon³

et al. 2013

CPAA

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“…This effect is marked for orally administered cimetidine, but not when the drug is given intravenously)221] Nizatidine, ranitidine and roxatidine do not change the pharmacokinetics of theophylline (table III). Investigators have reported differing results for famotidine, from concomitant famotidine reducing the clearance of theophylline [228] to it having no effect on clearance) 192,239) Propranolol is the only ~-adrenoreceptor antagonist that reduces the clearance of theophylline (30 to 52%), [170,214] Atenolol, metoprolol and nadolol do not appear to influence its elimination (table IV).…”

Section: Enzyme Inhibitionmentioning

confidence: 92%

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

Tröger

Meyer

1995

Clinical Pharmacokinetics

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Theophylline has been widely used as a bronchodilatory drug for the treatment of neonatal apnoea in premature newborns and patients with obstructive airways disease. The development of analytical equipment and procedures to determine the systemic concentration of theophylline renders it possible to improve the effectiveness of theophylline therapy and reduce the incidence of toxic and adverse effects. Since the beginning of the 1970s, endogenous and exogenous factors (e.g. age, blood pH, concomitant diseases and drug therapy, meal preparation procedure, nutritional habits, pregnancy, gender, smoking and, to a lesser extent, biorhythms), influencing nearly all parameters of theophylline pharmacokinetics have been described. Drug absorption depends on galenic formulation, drug delivery, nutritional habits and the chemical derivatives used. The mean plasma protein binding rates depend on the method of plasma protein determination: acidic blood pH values and advanced age may result in reduced plasma proteins. The volume of distribution depends primarily on age; it is 2-fold greater in newborns than in adults. Furthermore, changes in blood pH values, the plasma protein content and the administration of concomitant drugs may vary this parameter. Biotransformation is the most clinically important pharmacokinetic parameter. Hepatic metabolism accounts for 90% of the metabolism of theophylline. Essentially, 2 microsomal isoenzymes of the cytochrome P450 system appear to be responsible for the N-methylation and 8-hydroxylation of the drug. Age and concomitant disease are the major endogenous effectors influencing biotransformation of theophylline, whereas biorhythms, gender and pregnancy are of lesser importance. Exogenous factors, such as concomitantly administered drugs, smoking and nutritional factors, affect biotransformation by inducing or inhibiting the metabolising enzymes. Because of intra- and interindividual variability in the pharmacokinetics of theophylline, which may be increased by the presence of endogenous and/or exogenous effectors, it is necessary to supervise theophylline therapy by therapeutic drug monitoring if target concentrations are to be achieved.

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“…Most of the studies ascribed the amelioration of airway hyper-responsiveness to the anti-reflux effect of H2R antagonists on gastroesophageal tract, although some studies mentioned that the blockade of weak H2R signaling in airway tissue may also work in part. However, we noticed that several reports emphasized the influence of H2R antagonists on the disposition of theophylline in both healthy volunteers [31] and patients with airway disorders [32]. Although these results were thought to be related to CYP450-mediated metabolism, it could also be explained as impact on the xenobiotic transporter, such as EMT.…”

Section: Resultsmentioning

confidence: 96%

Extraneuronal Monoamine Transporter Mediates the Permissive Action of Cortisol in the Guinea Pig Trachea: Possible Involvement of Tracheal Chondrocytes

Wang

Qiu²,

Zheng³

et al. 2013

PLoS ONE

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Cortisol, a member of glucocorticoids, could potentiate the action of catecholamine by a non-genomic mechanism. Although this permissive effect has been well appreciated in the anti-asthmatic medication, the underlying signaling pathway has remained mysterious. Here, we show that extraneuronal monoamine transporter (EMT), a membraneous reuptake transporter for circulating catecholamine clearance, is the direct target of cortisol in its permissive effect. We found that BSA-conjugated cortisol, which functions as a cortisol but cannot penetrate cell membrane, enhanced the spasmolytic effect of β-adrenoceptor agonist (isoprenaline) in histamine-sensitized tracheal spirals of guinea pigs, and pharmacological inhibition of EMT with famotidine was powerful enough to imitate the permissive action of cortisol. To our surprise, EMT protein expression was high in the chondrocytes of tracheal cartilage, but was undetectable in tracheal smooth muscle cells. The functionality of EMT was further confirmed with measurement of catecholamine uptake by tracheal chondrocytes. Moreover, cortisol-initiated membrane signaling could activate protein kinase C (PKC), which phosphorylates EMT and induces its internalization via a lipid raft-dependent pathway. Both of the mechanisms slow down the reuptake process by chondrocytes, leading to extracellular catecholamine accumulation and results in a more profound adrenergic signaling activation in tracheal smooth muscle cells. Thus, an EMT-centered pathway was proposed to explain the permissive action of cortisol. Collectively, our results highlight the role of EMT in the crosstalk between glucocorticoid and catecholamine. EMT may represent a promising target for adrenergic signaling modulation.

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Comparative effect of famotidine and cimetidine on the pharmacokinetics of theophylline in normal volunteers.

Cited by 22 publications

References 12 publications

Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor

Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

Extraneuronal Monoamine Transporter Mediates the Permissive Action of Cortisol in the Guinea Pig Trachea: Possible Involvement of Tracheal Chondrocytes

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