Plasma Protein Binding Of Warfarin Research Articles

The effect of fenofibric acid on the pharmacokinetics and pharmacodynamics of warfarin in rats

1. Case reports have shown that coadministration of fenofibric acid (FA) could increase bleeding risks of warfarin, but the mechanisms remained unknown. We therefore investigated the pharmacokinetic and pharmacodynamic interaction between warfarin and FA in rats.2. Rats received warfarin alone (2 mg/kg) or coadministered with FA (100 mg/kg). FA significantly increased the exposure to warfarin, and decreased that to 7-hydroxywarfarin in rats nearly by two-fold, meanwhile increased Cmax and prolonged t1/2 of warfarin. Anticoagulant activity significantly increased, with prothrombin time (PT) up to 199 ± 33 s in coadministered group (approximately ten-fold compared with rats received warfarin alone). Incubation experiments illustrated FA inhibited CYP2C6 and CYP3A1/2 with the IC50 values of 6.98 and 16.14 μM, and inhibited the metabolism of warfarin (Ki value of 2.21 μM). Meanwhile, FA decreased the plasma protein binding of warfarin in vitro.3. Our data suggested that the altered pharmacokinetics and pharmacodynamics of warfarin in rats was primarily attributed to the inhibition of metabolism. Anticoagulant activity monitoring or warfarin dose lowering needs to be considered when patients are coadministered with FA.

Mechanism of Drug-Drug Interactions Between Warfarin and Statins

The anticoagulant drug warfarin and the lipid-lowering statin drugs are commonly co-administered to patients with cardiovascular diseases. Clinically significant drug-drug interactions (DDIs) between these drugs have been recognized through case studies for many years, but the biochemical mechanisms causing these interactions have not been explained fully. Previous theories include kinetic alterations in cytochrome P-450–mediated drug metabolism or disturbances of drug-protein binding, leading to anticoagulant activity of warfarin; however, neither the enantioselective effects on warfarin metabolism nor the potential disruption of drug transporter function have been well investigated. This study investigated the etiology of the DDIs between warfarin and statins. Liquid chromatography–mass spectrometry methods were developed and validated to quantify racemic warfarin, 6 of its hydroxylated metabolites, and pure enantiomers of warfarin; these methods were applied to study the role of different absorption, distribution, metabolism, and excretion properties, leading to DDIs. Plasma protein binding displacement of warfarin was performed in the presence of statins using equilibrium dialysis method. Substrate kinetics of warfarin and pure enantiomers were performed with human liver microsomes to determine the kinetic parameters (Km and Vmax) for the formation of all 6 hydroxywarfarin metabolites, inhibition of warfarin metabolism in the presence of statins, was determined. Uptake transport studies of warfarin were performed using overexpressing HEK cell lines and efflux transport using human adenocarcinoma colonic cell line cells. Fluvastatin significantly displaced plasma protein binding of warfarin and pure enantiomers; no other statin resulted in significant displacement of warfarin. All the statins that inhibited the formation of 10-hydroxywarfarin, atorvastatin, pitavastatin, and simvastatin were highly potent compared to other statins; in contrast, only fluvastatin was found to be a potent inhibitor of formation of 7-hydroxy warfarin. Uptake and efflux drug transporters do not play any role in these DDIs. The results showed that DDIs between warfarin and statins are primarily caused by cytochrome P-450 inhibition.

Induction of liver cytochrome P450s by Danshen–Gegen formula is the leading cause for its pharmacokinetic interactions with warfarin

Ethnopharmacological relevanceAlthough the increased usage of herbal medicine leading to herb–drug interactions is well reported, the mechanism of such interactions between herbal medicines with conventionally prescribed drugs such as warfarin is not yet fully understood. Our previous rat in vivo study demonstrated that co-administration of Danshen–Gegen Formula (DGF), a Radix Salvia miltiorrhiza (Danshen) and Radix Puerariae lobatae (Gegen) containing Chinese medicine formula recently developed for the treatment of cardiovascular disease, with warfarin could cause significant herb–drug interactions. The current study aims to explore the pharmacokinetics-based mechanism of the DGF–warfarin interactions during absorption, distribution and metabolism processes. Materials and methodsCaco-2 cell monolayer model and rat in situ intestinal perfusion model were used to study the DGF–warfarin interactions during the intestinal absorption processes. Male Sprague–Dawley rats were orally administered warfarin in presence and absence of DGF for consecutive 5 days. The microsomal activity and expression of the liver CYP isozymes were determined and compared among different treatment groups. Blood from the rats administered DGF was employed to evaluate effects of DGF on the plasma protein binding of warfarin. ResultsAbsorption studies demonstrated that DGF could potentially increase the intestinal absorption of warfarin (32% and 75% increase of warfarin Papp in Caco-2 and intestinal perfusion models, respectively) via altering the regional pH environment in GI tract. DGF administration could lead to significant increase in liver microsomal activity and mRNA expression of CYP1A1 and CYP2B1, indicating the potential induction on the liver metabolism of warfarin by DGF. Moreover, it has been proven by ex vivo study that the single-dose administration of DGF could decrease the protein binding of warfarin in plasma by at least 11.6%. ConclusionCollectively, current study demonstrated that DGF could significantly induce the liver phase I metabolism of warfarin, and to a less extent, potentially increase the intestinal absorption and decrease the plasma protein binding of warfarin. The inductive effects of DGF on the liver phase I metabolism of warfarin may be dominantly responsible for the DGF–warfarin pharmacokinetics interactions.

Sulfadimethoxine-bucolome interaction in rabbits: role of N4-acetylsulfadimethoxine, a major metabolite of sulfadimethoxine.

The role of N4-acetylsulfadimethoxine (N4-AcSDM), a major metabolite of sulfadimethoxine (SDM), in protein binding and pharmacokinetic interactions between SDM and bucolome (BCP) was investigated in rabbits. When SDM and BCP were intravenously co-administered, BCP indirectly reduced the serum protein binding of SDM by causing a marked increase of N4-AcSDM concentration in serum, and significantly increased the steady-state volume of distribution (Vss) and total body clearance (C1tot) of SDM. In addition, the co-administration of N4-AcSDM was found to increase Vss and C1tot of SDM. These results lead us to conclude that N4-AcSDM plays an important role in protein binding and pharmacokinetic interactions between SDM and BCP in rabbits. Several investigations have demonstrated that a metabolite plays an important role in drug-drug interaction. For example, Sellers et al. (1) reported that when warfarin and chloral hydrate are co-administered, a major metabolite of chloral hydrate, trichloroacetic acid, reduces the plasma protein binding of warfarin and enhances its anti-coagulant activity. Our previous paper (2) showed that probenecid indirectly reduces the plasma protein binding of sulfadimethoxine (SDM) by causing a marked increase in the plasma concentration of N4-acetylsulfadimethoxine (N4-AcSDM), which is a major metabolite of SDM (3) and strongly displaces SDM from its plasma protein binding sites (2). However, as yet the role of this metabolite in drug-drug interaction has not been fully examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered plasma protein binding of drugs in thyroid disease.

The plasma protein binding of propranolol and warfarin was studied in vitro by ultrafiltration in hyper- and hypothyroid patients both before and after treatment. The degree of binding of propranolol was significantly decreased in hyperthyroid patients and increased in hypothyroid patients, and was negatively correlated with serum thyroxine and the free thyroxine index. The plasma protein binding of warfarin was also decreased in hyperthyroid patients, but was unchanged in hypothyroid patients. These results suggest that the binding of both acidic and basic drugs may be altered by thyroid disease.

Plasma levels and protein binding of phenytoin during exercise in man: the effect of elevated free fatty acids.

Five healthy subjects performed submaximal physical exercise approximately 20 h after a single oral dose of phenytoin (5 mg/kg of the sodium salt). The plasma levels of free fatty acids (FFA) increased 2- to 3-fold in the post-exercise period. In spite of this, the degree of plasma binding of phenytoin and its total concentration in plasma were unaffected. Thus FFA at the levels reached (1.5-2.9 mEq/l), did not displace phenytoin from its binding sites on albumin. Furthermore, during the FFA peak the plasma protein binding of warfarin, as measured in vitro, did not decrease as compared to the pre-exercise period. These findings contrast to previous observations in rats and dogs, where FFA caused a considerable displacement of warfarin and phenytoin at relatively low FFA/albumin molar ratios.

Effect of heparin and fatty acids on the binding of quinidine and warfarin in plasma

After an intravenous injection of heparin, the plasma protein binding of warfarin was greatly increased while the binding of quinidine seemed to be less affected. The increased binding of warfarin seemed partly due to the release of plasma non-esterified fatty acids, NEFA, but the level of NEFA alone could not explain the interindividual variations of plasma warfarin binding. Addition in vitro of palmitic acid to serum demonstrated an increased binding of warfarin and an unaltered binding of quinidine up to a serum NEFA level of 3.0 meq/l. Albumin isolated from post heparin plasma revealed an increased binding affinity for warfarin at the warfarin high affinity binding sites, and a slightly depressed affinity for quinidine. The low affinity binding sites on the albumin molecule for both drugs did not seem to be influenced by NEFA.

Response to warfarin in hypothyroid rats

Effects of a single intravenous dose of warfarin in thyroidectomized rats were compared with responses of sham-neck operated, euthyroid and control rats. Control prothrombin times were similar in thyroidectomized and control rats. Prolongation of the one-stage prothrombin time after warfarin was less at 24 hr in the thyroidectomized rats than in the control rats. However, if the prothrombin response was examined over the duration of its effect, the response to warfarin was significantly greater in the thyroidectomized rats; plasma half-life of warfarin was significantly longer in thyroidectomized rats. No differences were noted in the calculated volumes of distribution, the plasma protein binding of warfarin, or in the total plasma protein and plasma albumin concentrations between thyroidectomized and control rats. These findings emphasize the point that the hypoprothrombinemic effects of indirect anticoagulants must be followed over the entire period of increased prothrombin time in order to reach valid conclusions about the interference of disease, simultaneously administered drugs, genetic and other factors. We conclude that hypothyroid rats are not resistant to the anticoagulant effect of warfarin, as previously reported, but actually are more sensitive than are normal rats.