No Effect of the Novel Antidiabetic Agent Nateglinide on the Pharmacokinetics and Anticoagulant Properties of Warfarin in Healthy Volunteers

Abstract

The novel hypoglycemic agent nateglinide is pharmacologically distinct from oral hypoglycemic agents such as sulfonylureas and repaglinide. The present study investigated the effects in healthy volunteers of multiple doses of nateglinide on the pharmacokinetics and pharmacodynamics of warfarin. The study comprised a randomized two-group, two-way crossover, open-label design in 12 healthy male subjects. One group of 6 subjects initially received a single oral dose of warfarin 30 mg and then, after a 7- to 14-day washout, received both warfarin and nateglinide (120 mgnateglinide, 10 min before meals for 4 days and a single dose of 30 mg warfarin on the second day). The alternate group of 6 subjects received treatments in the opposite order. Pharmacokinetic profiles were derived from plasma warfarin and nateglinide concentrations. Prothrombin measurements were evaluated in both periods as a measure of warfarin activity. When administered alone or in combination, there were no statistically significant differences in mean warfarin (R- and S-enantiomers) or nateglinide pharmacokinetic parameters. The concurrent administration of nateglinide and warfarin did not affect the maximal change in prothrombin time that follows warfarin administration. In this study, there was no evidence of an effect of coadministration of nateglinide on the pharmacodynamic action of warfarin or any pharmacokinetic interaction between warfarin and nateglinide.

Systematic Overview of Warfarin and Its Drug and Food Interactions

“…Forty-one new reports were rated as level I causation (highly probable) for an interaction, with 14 reporting potentiation (acetaminophen, 17 boldo-fenugreek, 18 ciprofloxacin, 16 citalopram, 19 diltiazem, 20 entacapone, 21 fenofibrate, 22 fish oil, 23 mango, 24 miconazole vaginal suppositories, 25 quilinggao, 26 sertraline, 27 voriconazole, 28 and zileuton 2 9 ), 5 reporting inhibition (etodolac, 30 mercaptopurine, 31 mesalamine, 32 ribavirin, 33 and trazodone 34 ), and 22 reporting "no effect" (anastrozole, 35 argatroban, 36 cilostazol, 37 clopidogrel, 14 donepezil hydrochloride, 38 eprosartan, 39 entacapone, 40 gemifloxacin, 41 levetiracetam, 42 losartan, 43 meloxicam, 44 metrifonate, 45 miglitol, 46 modafinil, 47 moexipril, 48 montelukast, 49 nateglinide, 50 nefazodone, 51 olestra, 12 pantoprazole, 52 sevelamer hydrochloride, 53 and vitamin E 13 ). For 38 drugs or foods, level II causation (probable) criteria were met, and for the remaining 41 drugs or foods, the evidence was even less conclusive.…”

(E)-1-[1-(6-Bromo-2-oxo-2H-chromen-3-yl)ethylidene]thiosemicarbazide

“…Thiosemicarbazide compounds exhibit various biological activities such as anti-bacterial, anti-fungal and especially antituberculosis . Apart from this, coumarins constitute an important class of compounds found throughout the plant kingdom and are known to have diverse activities such as anti-coagulants (Anderson et al, 2002, Tassies et al, 2002, anti-bacterial (Mitscher, 2002, Laffitte et al, 2002, anti-fungal (Moffett, 1964) and cytotoxicity (Weber et al, 1998) properties. The coumarin moiety and related derivatives are also reported to have importance as vasodilators (Hoult & Payá, 1996), anti-mutagenic agents (Pillai et al, 1999), scavengers of reactive oxygen species (Finn et al, 2004), as well as lipoxygenese and cyclooxygenese inhibitors (Kimura et al, 1985, Hofmanová et al, 1998.…”

“…For general background to and applications of the title thiosemicarbazide compound, see: Anderson et al (2002); Chulian et al (2009); Desai et al (1984); Finn et al (2004); Hofmanová et al (1998); Hoult & Payá (1996); Kimura et al (1985); Laffitte et al (2002); Mitscher (2002); Moffett (1964); Pillai et al (1999); Shukla et al (1984); Tassies et al (2002); Weber et al (1998). For the preparation, see: Moamen et al (2009).…”

Synthesis, reactions, antioxidant and anticancer evaluation of some novel coumarin derivatives using ethyl 2-(2-oxo-4-phenyl-2H-chromen-7-yloxy) acetate as a starting material

“…The cytotoxic activities of the coumarin derivatives were tested in several human tumor cell lines [1][2][3][4][5][6][7]. In addition, the antimicrobial, antitumor, anti-inflammatory, antimalarial and anti-HIV activities of hydrazide compounds on tumor cell lines have been observed and recently reported [8][9][10][11][12][13][14], Moreover, some synthetic oxadiazole derivatives exhibit a range of pharmacological activities [15][16][17][18].…”