Treatment with Ticlopidine Is Associated with Reduction of Cyclosporin A Blood Levels

Feriozzi, Sandro; Massimetti, Carlo; Ancarani, E

doi:10.1159/000064474

Cited by 7 publications

(4 citation statements)

References 4 publications

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“…There was no evidence of carcinogenicity among mice exposed to ticlopidine for 18 months in doses of 25,135 and 275 mg/kg/day orally, or rats exposed to ticlopidine for 2 years at doses of 10, 30, and 100 mg/kg/day orally 40 .…”

Section: Carcinogenicitymentioning

confidence: 89%

“…However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. It may be useful to remeasure phenytoin blood concentrations after combined administration with ticlopidine due to ticlopidine inhibition of phenytoin metabolism via CYP2C19 20,21 .CorticosteroidsAdministration of corticosteroids reverses ticlopidineinduced prolongation of bleeding time but does not alter ticlopidine-mediated inhibition of ADP-induced platelet aggregation22 .Cyclosporin ATreatment with ticlopidine is associated with a reduction in blood concentrations of cyclosporin A[23][24][25] .…”

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confidence: 99%

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Ticlopidine

Dusitanond¹,

Hankey²

2004

The Journal of Drug Evaluation

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Ticlopidine is an antiplatelet drug which inhibits the adenosine diphosphate (ADP) receptor on platelets, and thereby reduces platelet activation and aggregration, and subsequent serious vascular events in patients at risk of thrombotic events. ChemistryThe chemical name of ticlopidine hydrochloride is 5-[(2-Chlorophenyl)-methyl]-4,5,6,7-tetrahydrothieno [3,2-c] pyridinehydrochloride.The empirical formula of ticlopidine hydrochloride is C 14 H 14 ClNS-HCl ( Figure 1).Ticlopidine is a thienopyridine derivative and has a thienopyridine ring in its structure. It has a molecular weight of 300.25 daltons. It is a white crystalline powder which is freely soluble in water and methanol.It is sparingly soluble in methylene chloride, ethanol and buffer solutions above pH 6.0 and slightly soluble in acetone. An aqueous solution of ticlopidine has a pH of 3.6. Pharmacokinetic propertiesAbsorption Approximately 80-90% of an oral dose of ticlopidine is absorbed in healthy volunteers 1 . Absorption of ticlopidine is improved when the drug is administered with food 2 . Plasma concentrationsSingle dose A single 250 mg dose of ticlopidine produces a peak plasma concentration (Cmax) of between 0.31 and 0.70 mg/L at 1.7-2.0 h after administration in healthy volunteers 3-5 . Administration of a single 250 mg dose of [ 14 C]-ticlopidine in untreated subjects realises only 5% of the area under the plasma concentration-time curve (AUC) for plasma radioactivity during the first 8 h after administration. Repeated dosesRepeated doses of 250 mg bid of ticlopidine given to healthy volunteers produces steady-state plasma concentrations after 5-14 days, and values for Cmax of 0.89-1.42 mg/L 5,6 . After multiple dosing with nonlabeled ticlopidine, the proportion of ticlopidine to total radioactivity in plasma increases to approximately 15% of plasma radioactivity over 8 h 4 . The increase in ticlopidine concentrations and the increased proportion of total radioactivity after multiple dosing suggests that metabolism of ticlopidine is saturated after chronic dosing. This finding is consistent with multiple-dose pharmacokinetic studies of ticlopidine 5 . Influence of food and antacidAdministration of a single 250 mg dose of ticlopidine together with food results in 11% less time to reach Cmax, and the values for Cmax and AUC are 20% higher, compared with administration of ticlopidine after fasting 7 . Administration of ticlopidine with food is recommended to maximize gastrointestinal tolerance.In contrast, administration of ticlopidine with an antacid results in a significant decrease in AUC but no change in the rate of absorption, compared with adminstration after fasting 7 .

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Section: Carcinogenicitymentioning

confidence: 89%

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confidence: 99%

Ticlopidine

Dusitanond¹,

Hankey²

2004

The Journal of Drug Evaluation

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“…51,52 Not all studies have confirmed this interaction. 53 Currently, no data with TAC have been published.…”

Section: Antiplatelet Agentsmentioning

confidence: 99%

Drug Therapy in the Heart Transplant Recipient

2005

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With improving survival, the heart transplant recipient faces an increasing number of medical problems caused by both aging and the cumulative complications of immunosuppressive drugs. 1 The availability of new drugs to treat infection, obesity, hypertension, hyperlipidemia, renal insufficiency, diabetes, osteoporosis, gout, and malignancies has resulted in the heart transplant recipient and their physicians facing an almost overwhelming number of important drug-drug interactions. In parts 1 through 3 of this series, we reviewed commonly used immunosuppressive drugs and their pharmacology, as well as the common medical problems faced by the heart transplant recipient. In this article, we provide an overview of the mechanisms of common and important potential drug-drug interactions and guidelines for avoiding these interactions. Principles of Drug-Drug InteractionsThe risk for drug-drug interactions is increased by advanced age, polypharmacy, medications with a narrow therapeutic index, or medications requiring intensive monitoring. All of these factors except advanced age are present in the heart transplant recipient. A 10-fold interpatient variability may exist in the magnitude of a drug interaction resulting from patient-related and drug-related factors. 2 Patient-related factors predisposing to drug interactions include concomitant diseases, genetics, diet, and environmental exposures. For example, commonly used immunosuppressants, antifungal agents, and lipid-lowering medications are metabolized through the cytochrome P450 (CYP450) enzyme system and effluxed from cells by the multiple drug resistance transporter protein p-glycoprotein (P-gp). Both systems are found in the liver and gastrointestinal tract and exhibit genetic polymorphism. 2 The CYP450 enzymes belong to a superfamily of oxygenases; the primary purpose of these oxygenases is to add a functional group to a drug to increase its polarity and to promote its excretion from the body. If enzymes possess Ͼ40% homology, they are grouped together into families designated by an Arabic numeral (eg, the CYP1 family). Families are further divided into subfamilies, which are designated by a letter after the number (eg, CYP2C and CYP2D subfamilies); members of each subfamily have Ͼ55% homology with each another. Individual members are given an additional number (eg, CYP3A4) to identify a specific enzyme pathway. 2 CYP3A4 is particularly important because 60% of oxidized drugs, including the calcineurin inhibitors (CIs) cyclosporine (CSA) and tacrolimus (TAC), sirolimus (SIR), and everolimus (EVER), undergo biotransformation through this particular enzyme system. 3 P-gp is a membrane-bound glycoprotein belonging to the superfamily of ATP-binding cassette transporters. Like the CYP450 enzyme system, P-gp acts in a protective capacity by "effluxing" drug from the cell membrane or cytoplasm. P-gp density is highest within the small intestine, proximal tubules of the kidney, and biliary canalicular membranes. Some medications such as CIs and SIR use both the CYP450...

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“…It was reported that treatment with ticlopidine at the dose of 250 mg daily in kidney transplant patients caused significant reduction of cyclosporin A (CsA) blood levels (4, 5). In heart transplant patients treated with higher doses of ticlopidine 500mg daily, it was found to cause significant decrease of cyclosporine concentration but not in those treated with only 250mg daily (1, 2).…”

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confidence: 99%