Single-dose pharmacokinetics, pharmacodynamics and safety of AZD0837, a novel oral direct thrombin inhibitor, in young healthy male subjects.

OBJECTIVE: The novel oral anticoagulant AZD0837 is currently in clinical development for the prevention of stroke and systemic embolic events in patients with atrial fibrillation. AZD0837 is bioconverted to AR-H067637, a selective and reversible direct thrombin inhibitor. This first-time-in-man study (study code D1250C00001) investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD0837. METHODS: Healthy Caucasian male volunteers (n = 44, age 20 - 39 y) were enrolled into this study of single oral escalating doses of AZD0837 given in solution (15 - 750 mg, n = 4 per dose). PD was assessed by ex vivo measurements of activated partial thromboplastin time (APTT), ecarin coagulation time (ECT), thrombin time (TT) and thrombin generation in plasma. RESULTS: AZD0837 was rapidly absorbed, with a mean oral bioavailability of 22 - 52%, and bioconverted to the active form, AR-H067637. In fasting subjects, maximum plasma concentrations (Cmax) for AR-H067637 occurred approximately 1 h post-dosing and declined with a mean half-life of 9.3 h. The Cmax and area under the curve for AR-H067637 showed a low to moderate inter-individual variability of 16% and 28%, respectively, and exhibited a slight deviation from dose-proportionality. AZD0837 produced a dose-dependent prolongation of APTT, ECT and TT, and decreased maximum free thrombin activity. AZD0837 was generally well tolerated. CONCLUSIONS: AZD0837 single oral doses (15 - 750 mg) are well tolerated in healthy male subjects and exhibit favorable PK properties and reproducible effects on ex vivo coagulation time variables that support further clinical development.

The oral direct thrombin inhibitor, ximelagatran, an alternative for anticoagulant treatment during the puerperium and lactation.

OBJECTIVE: To determine the excretion of the oral direct thrombin inhibitor (oral DTI), ximelagatran, and its active form, melagatran, in human milk, and to thus evaluate the potential exposure of breastfed infants to melagatran. DESIGN: An open, single dose, single centre study. SETTING: Department of Antenatal Care, Primary Health Care South Bohuslän and Institute for the Health of Women and Children, Göteborg University, Sweden. SAMPLE: Seven healthy Caucasian breastfeeding women who were at least two months postpartum were studied. METHODS: The concentrations of ximelagatran, its two intermediates, and melagatran were determined using liquid chromatography-mass spectrometry, with the limit of quantification of 2 nmol L(-1) for human milk and 10 nmol L(-1) for plasma concentrations. MAIN OUTCOME MEASURES: Concentrations of ximelagatran, its intermediates and melagatran were measured in breast milk over 72 hours, and in plasma over 12 hours, after a single oral 36 mg dose of ximelagatran. RESULTS: Neither ximelagatran nor its intermediates were detected in human breast milk. Only trace amounts of melagatran were detected. The mean cumulative amount of melagatran excreted into breast milk over the 72-hour period after dosing with oral ximelagatran was 0.00091% of the administered dose of ximelagatran. Ximelagatran was well tolerated, with no clinically relevant changes in laboratory variables or vital signs. CONCLUSIONS: Trace levels of melagatran are excreted in human breast milk following administration of the oral DTI ximelagatran. The exposure of breastfed infants to melagatran appears to be low and is therefore unlikely to be of clinical concern.

Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis.

BACKGROUND: Thrombin plays a major role in thrombus formation through activation of platelets and conversion of fibrinogen to fibrin. OBJECTIVES: To investigate the antithrombotic effects of the oral direct thrombin inhibitor (DTI) ximelagatran and the parenteral DTI r-hirudin in humans. SUBJECTS AND METHODS: Healthy male volunteers randomized into four parallel groups each with 15 subjects received either ximelagatran (20, 40 or 80 mg orally) or r-hirudin (0.4 mg kg-1 intravenous bolus + infusion of 0.15 mg kg-1 h-1 for 2 h and 0.075 mg kg-1 h-1 for 3 h). Antithrombotic effects were assessed as changes in total thrombus area (TTA) and total fibrin area (TFA) from baseline, using the Badimon perfusion chamber model at baseline and 2 h and 5 h after drug administration. RESULTS: Two hours postdosing, ximelagatran showed antithrombotic effects at both high and low shear rates (TTA% of mean baseline value +/- SEM was 76 +/- 13% and 71 +/- 17% [both P < 0.05] for the 20-mg dose, 85 +/- 11% [P > 0.05] and 62 +/- 15% [P < 0.05] for the 40-mg dose and 60 +/- 11% and 26 +/- 7% [both P < 0.05] for the 80-mg dose, respectively). r-Hirudin also showed a significant antithrombotic effect at high and low shear rates (76 +/- 11% [P = 0.05] and 57 +/- 17% [P < 0.05] of baseline values, 2 h postdosing, respectively). The inhibitory effects on TFA were similar to those on TTA. CONCLUSIONS: The oral DTI ximelagatran shows antithrombotic effects under both high and low shear conditions. The antithrombotic effect of 40-80 mg ximelagatran appeared comparable to that of parenterally administered r-hirudin, which has been previously demonstrated to be clinically effective in acute coronary syndromes.

Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man.

H 335/25, a 4-amino quinoline, belongs to a new class of reversible gastric acid pump inhibitors. A potential advantage of such drugs over the irreversible proton pump inhibitors (PPIs) is better control over the effect-time profile. Dose escalation studies were performed to characterize the effect on acid secretion in dogs (n=24) and healthy male subjects (n=12). The effect-time profile was delayed compared to the concentration-time profile. A model-based approach, using non-linear mixed effects modelling, was applied to quantify and elucidate the mechanism for the delayed effect. Three different models were investigated: (1) a slow equilibration preceding the formation of drug-enzyme complex, modelled by an effect-compartment, (2) a slow equilibration between free drug, free enzyme and drug-enzyme complex, described by a kinetic binding model, and (3) a delay between enzyme inhibition and the measured response, described by an indirect response model. Model 2 was shown to be superior to models 1 and 3, for both dog and human data. The dissociation rate constant, k(off), was estimated to be 0.85 and 0.88 h and the calculated equilibration constant, K(d), was 160 and 250 nM in dog and man, respectively. Simulations of the predicted time-course of the effect beyond the 4-5-h observation period was similar for the three models.

Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease.

AIMS: The purpose of this study was to characterize the relationship between the degree of anticoagulation, assessed by APTT, and the plasma concentration of inogatran in healthy subjects and in patients with coronary artery disease. METHODS: Data from five phase I studies in 78 healthy males and two phase II multicentre studies in 948 patients of both sexes with unstable angina pectoris or non-Q-wave myocardial infarction were evaluated. A total of 3296 pairs of concentration-APTT samples were obtained before, during, and after intravenous infusions of inogatran. Mixed effects modelling was used for population pharmacodynamic analysis of the drug effect and for describing the variability in baseline APTT. RESULTS: The population mean baseline APTT was 29 s, but large variations between individuals (s.d. 3.6 s) were observed. The variability between studies (1.3 s) and centres (1.8 s) were of less importance, though statistically significant. APTT increased in a nonlinear manner with increasing inogatran concentration and the relationship was well described by a combined linear and Emax model. A significant part of the overall variability could be ascribed to the APTT reagent and equipment used at the different study centres. These method-dependent differences were compensated for by including the lower limit of the normal reference range as a covariate, affecting both baseline and Emax, in the model. For the typical healthy subject and patient, the method-corrected population mean parameters were: APTTbaseline 35 and 31 s, slope 8.0 and 5.8 s x l x micromol(-1), Emax 36 and 34 s, and EC50 0.54 and 0.72 micromol x l(-1), respectively. The model predicted plasma concentration needed to double the APTT from the baseline value was 1.25 and 1.45 micromol x l(-1) in the healthy volunteer and patient, respectively. CONCLUSIONS: The nonlinear relationship between APTT and inogatran concentration in plasma was well described by a combined linear and Emax model. Pooling of data was made possible by incorporating a centre-specific characteristic of the assay method in the model. Patients had lower baseline APTT and appeared to have less pronounced effect of inogatran than young healthy subjects.

A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog.

A turnover model for irreversible inhibition of gastric acid secretion by omeprazole in gastric fistula dogs was developed using data from studies with both short- and long-term measurement periods. In the short-term experiments, after stimulation of acid secretion with histamine, the dogs were infused i.v. with omeprazole and acid secretion was measured for 5 h. Dose and infusion times were varied to produce different concentration-time profiles and schedule dependence in the inhibitory effect of omeprazole was observed. In the long-term experiments, dogs were given single intraduodenal doses, which inhibited the acid secretion for several days. Combining the short-term and long-term data allowed the observation of a biphasic recovery of acid secretion that was described by the turnover model. Second order association rate constants (k(ome)) for the covalent binding of omeprazole to H(+),K(+)-ATPase were estimated to 11 and 3.0 l/micromol/h for the i.v. and intraduodenal experiments, respectively. The apparent turnover rate constant of the enzyme (k(out)) was 0.013 h(-1) and the corresponding half-life of inhibition of acid secretory capacity was 54 h. The potency, calculated as k(out) over k(ome), was 4.3 and 1.2 nM for the intraduodenal and i.v. doses, respectively. Allometric scaling of the model resulted in trustworthy predictions for observations previously done in humans. The model predicted a good correlation between maximal inhibitory effect and exposure (area under the plasma concentration curve). The time dependence in this relation was also predicted by the model.

Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT.

Forty-eight patients with acute proximal deep vein thrombosis (DVT) were randomised to intravenous infusions for 4 to 6 days with melagatran, a novel synthetic low molecular weight thrombin inhibitor, or unfractionated heparin adjusted by the activated partial thromboplastin time (APTT). The aim of the study was to investigate the pharmacokinetics, pharmacodynamics and the safety of melagatran therapy at three different doses. Steady-state plasma concentrations were rapidly achieved and maintained throughout the infusion period. The mean plasma concentrations in the low, medium and high dose groups were 0.17, 0.31 and 0.53 micromol/l, respectively. The prolongation of APTT was stable during the melagatran infusions and correlated to the plasma concentration. Phlebographically verified regression of thrombus size measured as decrease in Marder score was seen after 4 to 6 days in 8 of 12 patients, 6 of 12 patients and 5 of 11 patients in the low, medium and high dose groups of melagatran and in 5 of the heparin-treated patients. In the low dose group with melagatran, thrombus extension was seen in one patient. At the dose levels studied, melagatran was well tolerated with no clinically significant bleeding problems, suggesting that melagatran could safely be given to patients suffering from DVT.

Animal pharmacokinetics of inogatran, a low-molecular-weight thrombin inhibitor with potential use as an antithrombotic drug.

Pharmacokinetics, excretion, and metabolism of inogatran, a low-molecular-weight thrombin inhibitor, were studied in the rat, dog, and cynomolgus monkey. After intravenous administration the half-life was short in all three animal species, due to a small volume of distribution and a relatively high clearance. At doses of 0.1-5 mumol kg-1, the mean residence time was about 10 min in the rat, 35 min in the dog, and 20 min in the cynomolgus monkey. The oral bioavailability of inogatran was incomplete, presumably due to a low membrane permeability, and dose dependent. The bioavailability was 4.8% at 20 mumol kg-1 and 32-51% at 500 mumol kg-1 in rats, 14% at 10 mumol kg-1 and 34-44% at 150 mumol kg-1 in dogs, and 2.1% at 1 mumol kg-1 in cynomolgus monkeys. The radioactivity excreted in urine and faeces was predominantly unchanged inogatran. After intravenous administration the percentage of the radioactivity recovered in faeces was about equal to or higher than the urinary recovery, which indicates biliary excretion of inogatran. After oral dosing, most of the dose was excreted in faeces, as expected from the estimates of oral bioavailability. The plasma protein binding of inogatran in rat, dog, and human plasma, was 20-28%. The blood-plasma concentration ratio was 0.39-0.56, indicating limited distribution into red blood cells.

Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice.

The effects of naringenin, quercetin and kaempferol, flavonoids found in grapefruit as glycosides, on the metabolism of nifedipine and the enantiomers of felodipine were studied in microsomes from rat and human liver. Flavonoid concentrations of 10, 50 and 100 mumol/l were added to rat liver microsomes. The metabolism of nifedipine, (R)- and (S)-felodipine was inhibited to a similar extent, and the inhibition was dependent on the chemical structure and the concentration of flavonoid. Naringenin had lower inhibitory potency than quercetin and kaempferol. These flavonoids exhibited the same order of inhibitory potency in human liver microsomes. No inhibition of naringenin was found, however, until higher concentrations, 300 and 500 mumol/l, were added. A likely mechanism is inhibition of cytochrome P-450 IIIA4, the isoenzyme that catalyzes the oxidation of the dihydropyridine ring to form the corresponding pharmacologically inactive pyridine metabolite. This is a predominant metabolic step that determines the extent of first-pass extraction of dihydropyridines. Grapefruit juice has been shown recently to increase the p.o. bioavailability of the dihydropyridine calcium antagonists nifedipine and felodipine. The interaction may be explained by an inhibition of the first-pass metabolism by flavonoids in grapefruit juice. Furthermore, the results indicate that the rat may be used for in vivo studies of interactions between flavonoids and dihydropyridines or other drugs that are metabolized by cytochrome P-450 IIIA4.

Stereoselective metabolism of felodipine in liver microsomes from rat, dog, and human.

Felodipine, a 1,4-dihydropyridine derivative, is a potent, vasoselective calcium antagonist that is used clinically as a racemic mixture of two stereoisomers. In the rat, dog, and human, the bioavailability of an oral dose is about 15% because of high first-pass metabolism. Oxidation of the dihydropyridine ring to the corresponding achiral, pharmacologically inactive pyridine metabolite is the predominant metabolic step. In the liver, this metabolism is catalyzed by cytochrome P-450. In the present study, the metabolism of (R)- and (S)- felodipine was compared in vitro in liver microsomes from rats, dogs, and humans. Slightly higher rates of metabolism were found for the (S)-enantiomer in rat and dog liver microsomes. However, no significant differences were observed in the Michaelis-Menten parameters, Vmax or KM. In human liver microsomes, the (R)-enantiomer was metabolized more readily than (S)-felodipine. The mean value of KM was lower for (R)-felodipine, while the Vmax values of the enantiomers were similar. The intrinsic clearance, defined as the ratio of Vmax and KM, was about two times higher for (R)-felodipine. Assuming complete absorption and that the bioavailability is determined by the first-pass metabolism in the liver, these in vitro results suggest that the bioavailability of (S)-felodipine in vivo is about two times higher than that of (R)-felodipine.

Pharmacokinetics of the enantiomers of felodipine in the dog after oral and intravenous administration of a pseudoracemic mixture.

1. A pseudoracemic mixture of deuterated (S)-felodipine and unlabelled (R)-felodipine was administered as single i.v. or oral doses to four dogs. Plasma concentrations of the enantiomers and their corresponding pyridine metabolites were determined by g.l.c.-mass spectrometry. 2. No isotope effects were observed after oral administration of equimolar amounts of deuterated and unlabelled (S)-felodipine. 3. The pharmacokinetic parameters of the enantiomers were similar after i.v. administration, indicating that the disposition of felodipine was not stereoselective. 4. After oral administration the bioavailability of (R)-felodipine was slightly higher than that of (S)-felodipine in two of the dogs, presumably due to a lower first-pass extraction of the (R)-enantiomer, while no difference was observed in the other two dogs. 5. No substantial differences in Cmax or AUC were observed between the deuterated and unlabelled pyridine metabolites, indicating that the oxidative clearances of the felodipine enantiomers were similar.

Pharmacokinetics in the rat and the dog of a nonionic nitroxide contrast agent for magnetic resonance imaging.

Nitroxides are paramagnetic stable free radicals that have demonstrated effectiveness as contrast agents in proton magnetic resonance imaging (MRI). The pharmacokinetics and metabolic fate, determinants of the time course of MRI contrast enhancement, of a new nonionic pyrrolidine nitroxide derivative, TAP (2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carbonic acid-(2,3-dihydroxy-1-hydroxymethyl)-amide), were evaluated in the rat and the dog. A biexponential decline of the blood concentration of TAP was observed in both species after intravenous administration of 0.1- and 2.5-mmol/kg doses. The clearances in the rat, estimated after the low and high doses (15.4 +/- 2.0 and 15.3 +/- 1.4 mL/min.kg, respectively), were about twofold higher than those observed in two beagles (7.4 and 7.1 mL/min.kg for Dog #1 and 6.3 and 6.0 mL/min.kg for Dog #2). The hydroxylamine of TAP, formed by a one-electron reduction of the nitroxide moiety, was the only metabolite observed. This bioreduction of TAP has implications for its use as a MRI contrast agent because the diamagnetic hydroxylamine lacks contrast enhancing activity. In both animal species, the urinary recoveries of the dose as unchanged TAP and its hydroxylamine were essentially complete for the 24-h urine collections (92 to 98% and 83 to 95% for the rats and the dogs, respectively). Anticipated conjugative metabolism of the hydroxyl-containing side chain of TAP was not observed. Renal excretion of unchanged TAP was the predominant route of elimination, as renal clearance was estimated to be between 47 and 89% of total clearance in the dogs. Bioreduction in vivo was slower than that expected from the observed reduction of TAP in vitro in ascorbic acid solution and in rat liver and kidney homogenates.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of ionic and non-ionic nitroxide spin labels for urographic enhancement in magnetic resonance imaging.

Two nitroxide spin labels (NSL) were compared for in vitro relaxivity and in normal rats for efficiency of urographic enhancement. One of the NSL, PCA, a pyrrolidinyl agent, was ionic and one, NAT, was a non-ionic pyrrolidinyl NSL with multiple hydroxyl substituents for water solubility. Using both NSLs the renal medulla and papilla were noted to show greater contrast enhancement than the cortex, with a maximum enhancing effect between 5 and 15 minutes. Using doses of 1.0 and 2.5 mmol/kg, more than 100 per cent increases in spin echo intensities above the baseline were observed. The lowest tested dose of 0.1 mmol/kg showed an easily detectable enhancing effect for NAT. The good contrast enhancing properties of NAT, considered together with its better acute tolerance, justifies further investigation of this non-ionic compound.

Metabolic fate in the dog of the nitroxide moiety in a compound with potential utility as a contrast agent in MRI.

Nitroxides, paramagnetic compounds with demonstrated effectiveness as contrast agents in proton magnetic resonance imaging, shorten the relaxation times of protons and therefore cause an increase in image intensity in tissues into which they distribute. In this study, the metabolic fate of the nitroxide moiety was examined in the dog using a pyrrolidine nitroxide derivative, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid, for which contrast-enhancing properties have been previously studied in animals. After radiolabeling by microwave discharge in the presence of tritium gas, the compound was administered intravenously to a dog. Ninety-four percent of the radioactivity injected was recovered in urine within 3 days; the majority (90%) was excreted during the first 6 h. The radioactivity in the urine was identified as either the unchanged nitroxide or its corresponding hydroxylamine. Neither complete reduction of the nitroxide moiety to the amine nor any other metabolic transformation was observed.

Nonenzymatic bioreduction in rat liver and kidney of nitroxyl spin labels, potential contrast agents in magnetic resonance imaging.

Paramagnetic nitroxyl spin labels have potential clinical utility as contrast agents in proton magnetic resonance imaging. Reduction of the nitroxyl moiety in vivo results in the formation of the diamagnetic hydroxylamine, which lacks contrast-enhancing activity. Bioreduction is therefore an important determinant of the imaging behavior of these agents. Both enzymatic and nonenzymatic reduction mechanisms have been suggested for nitroxyl spin labels. This study examines the nonenzymatic mechanisms in rat liver and kidney, mammalian tissues that demonstrate high reducing activity. Protein-free preparations, obtained by heat precipitation or ultrafiltration of rat liver and kidney homogenates, were used to test piperidine and pyrrolidine nitroxyl spin-label derivatives, for which imaging properties and bioreduction had previously been examined. For the piperidine derivative, the initial reduction rates in ultrafiltrates and supernatant fluids were 25-60% of those in whole liver and kidney homogenates. However, the pyrrolidine derivative was reduced at rates much slower than those in whole tissue homogenates. The reduction in whole tissue homogenates was NADPH-dependent, while reduction in ultrafiltrates was unaffected by the addition of NADPH. Preincubation of the ultrafiltrates and supernatant fluids with ascorbic acid oxidase caused almost complete inhibition of the reduction. The reduction rates of these nitroxyl derivatives were determined in ascorbic acid solution; second order rate constants were 0.45 +/- 0.04 and 0.0042 +/- 0.001 mM-1 min-1 for the piperidine and pyrrolidine derivatives, respectively. The concentrations of ascorbic acid in the supernatant fluids and ultrafiltrates of rat liver and kidney were then predicted from the observed reduction rates and found to be virtually identical with those from spectrophotometric determinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Human erythrocyte membrane permeability and nitroxyl spin-label reduction.

Nitroxyl spin labels are paramagnetic compounds that have demonstrated utility as contrast enhancing agents in proton magnetic resonance imaging. The time-course of contrast enhancement depends on distribution and elimination of these agents. Reduction, resulting in formation of the diamagnetic hydroxylamine, is the major metabolic pathway observed in vivo. This bioreduction has implications for the design of contrast agents and for understanding their imaging behavior. Bioreduction has been shown to occur, at least in part, intracellularly. As such, cell membrane permeability to nitroxyl spin labels may influence their bioreduction. In this study, this influence was examined using eight nitroxyl derivatives and the human erythrocyte suspension as a model biomembrane system. Ionizable weak acids and bases were found to equilibrate rapidly across the erythrocyte membrane with half-times of equilibration ranging from less than 10 s to 1.6 min. These derivatives had low octanol:buffer distribution coefficients and were extensively ionized at the pH of the system (7.0). A strong acid, a phosphate ester, and a quaternary amine derivative were excluded by the cell membrane. Reduction of nitroxyl spin labels by the erythrocyte was shown to occur intracellularly. Except for the impermeable probes, the reduction rate was slow in comparison with the membrane penetration rate. The structural dependence of reduction rate was unrelated to penetration rate but correlated well with that observed in other reducing systems, namely, ascorbic acid solution and rat tissue homogenates.

Pharmacokinetics of two prototype nitroxide spin labels for contrast enhancement in magnetic resonance imaging.

Two nitroxide spin labels called PCA and TES have been used experimentally as contrast enhancing agents in magnetic resonance imaging. Pharmacokinetic data for these nitroxides, after intravenous administration to three dogs at two dose levels (0.1 and 2.5 mmole/kg), are presented. In this dose range, the clearance (13 ml/ min-kg) and half-life (22 min) of PCA stayed almost constant while TES clearance decreased (28 to 12 ml/min-kg) and half-life increased (8 to 17 min) with dose. The urinary recovery, determined from the sum of the nitroxide and its corresponding hydroxylamine, was 85 to 90% for both PCA and TES. PCA was investigated in more detail because of its lower clearance value and its lack of dose-dependence. The major pathways of elimination are renal excretion and metabolic reduction to the corresponding hydroxylamine which is eliminated by renal excretion. We estimated renal clearance of both PCA (5.5 ml/ min-kg) and its hydroxylamine (3.7 ml/min-kg) to be close to glomerular filtration rate (4 ml/min-kg) in the dog, while the metabolic clearance (7.5 ml/min-kg) was slightly higher. Approximately 35 % of the administered dose of PCA was excreted unchanged and half was reduced in the body.

Pharmacokinetics and metabolic fate of two nitroxides potentially useful as contrast agents for magnetic resonance imaging.

Paramagnetic nitroxyl-containing compounds have been useful as contrast agents in magnetic resonance imaging (MRI) experiments in animals. Preliminary information on the metabolic fate, pharmacokinetic behavior, stability in tissues, and chemical reduction of two prototypic nitroxides, PCA and TES, is presented. In the dog TES was eliminated more rapidly than PCA. More than 80 % of the dose of both nitroxides was recovered in urine within 6 hours. Nitroxides were reduced in vivo to their corresponding hydroxylamines. No other metabolite was observed. Measured reducing activity in tissue homogenates was greater in liver or kidney than in brain, lung or heart. In each tissue PCA was more stable than TES. PCA was also more resistant to reduction by ascorbic acid at physiologic pH. These preliminary results favor the use of PCA, a pyrrolidinyl nitroxide, over TES, a piperidinyl nitroxide, for MRI contrast enhancement.