Robert A. O'Reilly

The mechanism of the interaction between amiodarone and warfarin in humans

Amiodarone decreased the total body clearance of both (R)‐ and (S)‐warfarin in normal subjects but did not change volumes of distribution. Warfarin excretion products were quantified and clearance and formation clearance values calculated. Amiodarone and metabolites inhibited the reduction of (R)‐warfarin to (R,S)‐warfarin alcohol‐1 and the oxidation of both (R)‐ and (S)‐warfarin to phenolic metabolites. Inhibition of warfarin hydroxylation by amiodarone in human liver microsomes was compared with the in vivo results. In agreement, the in vitro data indicates that amiodarone is a general inhibitor of the cytochrome P450 catalyzed oxidation of both enantiomers of warfarin, but the metabolism of (S)‐warfarin is more strongly inhibited than that of (R)‐warfarin. These data suggest that the enhanced anticoagulant effect observed when amiodarone and warfarin are coadministered is attributable to inhibition of P4502C9, the isozyme of P‐450 primarily responsible for the conversion of (S)‐warfarin to its major metabolite, (S)‐7‐hydroxywarfarin.

Studies on Coumarin Anticoagulant Drugs Initiation of Warfarin Therapy Without a Loading Dose

Thirty normal subjects were given a single loading dose of warfarin sodium, 1.5 mg/kg of body weight. The drug was metabolized slowly (mean biological half-life, 47 hr) and showed a prolonged biological effect (over 6 days). In two separate experiments no loading dose was given; instead, daily doses of 15 mg and 10 mg were administered to 15 of the subjects. The prothrombin complex responses were compared with those obtained in the same subjects after the large loading dose. The mean time in days to reach the therapeutic range (prothrombin complex activity<35% of normal) was 1.1 days with the dose of 1.5 mg/kg of body weight, 2.7 days with the dose of 15 mg/day, and 5.2 days with 10 mg/day. With all three methods the therapeutic range was reached soon after a level of warfarin of 2 mg/L plasma was attained.The rates of fall of the four vitamin K-dependent clotting factors (II, VII, IX, and X) with the large loading dose and with the daily dosage of 15 mg were compared in six of the subjects. With the loading dose, factor VII activity was less during the first 48 hr, but there was no other significant difference between the two methods of drug administration in the amount of reduction of any of the four factors.Since the role of factor VII in thrombogenesis is questioned, these results provide a rational basis for the induction of prophylactic anticoagulant therapy without large loading doses of warfarin. Avoidance of the customary loading dose should reduce the danger of hemorrhage, particularly in patients who are sensitive to the drug because of advanced age, sepsis, liver disease, congestive heart failure, or recent surgery or trauma.

HEREDITARY TRANSMISSION OF EXCEPTIONAL RESISTANCE TO COUMARIN ANTICOAGULANT DRUGS. THE FIRST REPORTED KINDRED.

THE variability of response of human beings to many drugs is usually continuous and gives a unimodal frequency-distribution curve for the drug action measured. These unimodal distribution curves ar...

Studies on the Coumarin Anticoagulant Drugs: Interaction of Human Plasma Albumin and Warfarin Sodium

In studies by continuous flow electrophoresis the coumarin anticoagulant drug warfarin sodium was found to be bound solely to the albumin fraction of the plasma proteins. The interaction was studied in detail by equilibrium dialysis of solutions of crystalline human plasma albumin and warfarin sodium. Analysis of the data showed that albumin possesses a single strong binding site for warfarin with an association constant of 154,000 at 3 degrees C and secondary classes of several sites with a much lower affinity. The free energy of binding for the first anion determined at 3 degrees and 37 degrees C was -6.54 and -7.01 kcal per mole, respectively. The standard enthalpy change for the interaction was -3.48 kcal per mole, and the entropy change was +11.2 U. The negative enthalpy change was surprisingly large and the positive entropy change small for an anion-albumin interaction, suggesting significant nonionic binding. The inability to saturate the albumin binding sites, even when high concentrations of warfarin were used, is consistent with a reversible configurational alteration of the albumin molecule during the binding process. The thermodynamic data indicate that the albumin binding sites for warfarin sodium are formed during the process of binding, rather than being performed as in antigen-antibody reactions. The strength of the binding process suggests that many of the pharmacodynamic characteristics of warfarin sodium in man are determined by its strong interaction with plasma albumin. Such correlations of the physicochemical interactions and biologic effects of the coumarin anticoagulant drugs should lead to a better understanding of their mechanisms of action.

Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans

To evaluate a stereoselective interaction for amiodarone and racemic warfarin, we performed a prospective study with its separated enantiomorphs. Single oral doses of racemic warfarin, 1.5 mg/kg, were administered to six normal subjects, with and without oral amiodarone, 400 mg daily, for the hypoprothrombinemic duration. Both the hypoprothrombinemia (P < 0.001) and plasma warfarin concentrations (P < 0.01) were significantly increased. The experiments were repeated separately with the R‐ and S‐warfarin enantiomorphs. S‐warfarin with amiodarone significantly increased both the hypoprothrombinemia (P < 0.001) and plasma warfarin concentrations (P < 0.01). R‐warfarin with amiodarone significantly increased both the hypoprothrombinemia (P < 0.001) and plasma warfarin concentrations (P < 0.001). Thus amiodarone augmented the anticoagulant effect nonstereoselectively by reduced metabolic clearance of both warfarin enantiomorphs. Amiodarone and racemic warfarin can be a dangerous combination, particularly when either drug is added to a stabilized regimen of the other drug, unless the prothrombin times are monitored carefully.

Stereochemical aspects of warfarin drug interactions: Use of a combined pharmacokinetic-pharmacodynamic model

To apply a combined pharmacokinetic‐pharmacodynamic model to data from warfarin drug interaction studies.

The binding of sodium warfarin to plasma albumin and its displacement by phenylbutazone.

Modulation of the binding of drugs to plasma albumin is an important subject because of the serious clinical implications. The oral anticoagulant drugs are ideal agents for studying this phenomenon because their marked degree of binding to albumin produces significant displacement by other highly bound drugs. Furthermore, both the pharmacologic effect and the levels of oral anticoagulants in plasma can be quantitated readily. In addition to the intrinsic value of studying the albumin binding of oral anticoagulants, they also can provide an insight into the interaction of drugs with the receptor sites for pharmacologic activity. In this review, the number and strength of the binding sites on the albumin molecule for several oral anticoagulant drugs are considered. The albumin binding of warfarin precursors and metabolites is examined to further characterize the albumin binding sites for oral anticoagulants. The variation of the binding strength with changes in temperature, pH, and ionic strength of the supporting medium to evaluate the thermodynamic parameters of the interaction is recorded. The confirmation of these thermodynamic studies of the warfarin-albumin interaction by direct calorimetric measurement is reported. The impact of phenylbutazone on warfarin metabolism is presented, particularly the alteration of its albumin binding, its pharmacokinetic behavior, and its hypoprothrombinemic effect.

The Second Reported Kindred with Hereditary Resistance to Oral Anticoagulant Drugs

Abstract In this second reported kindred of hereditary resistance to oral anticoagulant drugs the propositus required 75 to 80 mg of sodium warfarin a day (25 standard deviations above the average ...

Interaction of Chronic Daily Warfarin Therapy and Rifampin

To evaluate the interaction between the antibiotic rifampin and the anticoagulant warfarin during chronic therapy, eight normal subjects were given daily doses of warfarin for 21 days to achieve therapeutic hypoprothrombinemia. Daily blood samples were analyzed for one-stage prothrombin activity and for warfarin content spectrophotometrically and chromatographically. One month later, the same warfarin dose was repeated plus rifampin, 600 mg a day orally. For the last 10 days of every experiment, there was a highly significant lessening of both the hypoprothrombinemic effect (P less than 0.001) and the blood levels of warfarin (P less than 0.001). No significant difference in the warfarin levels was found between the spectrophotometric and chromatographic methods. It is concluded that rifampin markedly decreases the hypoprothrombinemic effect of warfarin during long-term therapy by enhancing its elimination from plasma. This conclusion was reinforced by finding increased amounts of warfarin metabolites in urine and stool.

The hyperviscosity syndrome: I. In IgG myeloma. The role of protein concentration and molecular shape

The hyperviscosity syndrome is an uncommon complication in IgG myeloma. Its occurrence has been ascribed to the presence in the serum of high molecular weight polymers of the IgG proteins. Three patients with IgG myeloma and the clinical hyperviscosity syndrome were investigated, none of whom had IgG polymers in the serum by analytical ultracentrifugation. Relative serum viscosity in these patients ranged from 10 to 17.4 (normal 1.4-1.8). The total serum proteins ranged from 14 to 19 g/100 ml of which 10 to 17 g/100 ml was IgG globulin. Physicochemical studies of two of the isolated myeloma proteins indicated that they were of normal molecular weight (near 158,000 and 162,000). Protein Ca had a normal molecular radius (52.2 A) and configuration, (intrinsic viscosity of 5.5 cc/g, frictional ratio 1.48), but was present in very high concentration in the serum. Protein Pur had an increased molecular radius (58.2 A) and was asymmetrical (intrinsic viscosity 10.2 cc/g, frictional ratio 1.63). These results indicate that the concentration and molecular configuration of the myeloma protein are important determinants of the presence or absence of the hyperviscosity syndrome.