Plasma Radioactivity Half-life Research Articles

Radiolabel Uncovers Nonintuitive Metabolites of BIIB104: Novel Release of [14C]Cyanide from 2-Cyanothiophene and Subsequent Formation of [14C]Thiocyanate.

BIIB104 (formerly PF-04958242), N-((3S,4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide, is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator investigated for the treatment of cognitive impairment associated with schizophrenia. Preliminary in vitro metabolism studies with non-radiolabeled BIIB104 in rat, dog, and human liver microsomes (RLM, DLM, and HLM) showed O-dealkylation in all three species, tetrahydrofuran hydroxylation dominating in DLM and HLM, and thiophene hydroxylation prevalent in RLM. However, a subsequent rat mass balance study with [nitrile-14C]BIIB104 showed incomplete recovery of administered radioactivity (∼80%) from urine and feces over 7 days following an oral dose, and an exceptionally long plasma total radioactivity half-life. Radiochromatographic metabolite profiling and identification, including chemical derivation, revealed that [14C]cyanide was a major metabolite of [nitrile-14C]BIIB104 in RLM, but a minor and trace metabolite in DLM and HLM, respectively. Correspondingly in bile duct-cannulated rats, [14C]thiocyanate accounted for ∼53% of total radioactivity excreted over 48 hours postdose and it, as an endogenous substance, explained the exceptionally long plasma radioactivity half-life. The release of [14C]cyanide from the 2-cyanothiophene moiety is postulated to follow an epoxidation-initiated thiophene-opening based on the detection of non-radiolabeled counterpart metabolites in RLM. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate. Additionally, the potential cyanide metabolite of nitrile-containing drug molecules may be detected in liver microsomes with liquid chromatography-mass spectrometry following a chemical derivatization. SIGNIFICANCE STATEMENT: Using [nitrile-14C]BIIB104, non-intuitive metabolites of BIIB104 were discovered involving a novel cyanide release from the 2-cyanothiophene motif via a postulated epoxidation-initiated thiophene-opening. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate.

Mass Balance and Metabolite Profiling of Steady-State Faldaprevir, a Hepatitis C Virus NS3/4 Protease Inhibitor, in Healthy Male Subjects

The pharmacokinetics, mass balance, and metabolite profiles of faldaprevir, a selective peptide-mimetic hepatitis C virus NS3/NS4 protease inhibitor, were assessed at steady state in 7 healthy male subjects. Subjects received oral doses of 480 mg faldaprevir on day 1, followed by 240 mg faldaprevir on days 2 to 8 and 10 to 15. [14C]faldaprevir (240 mg containing 100 μCi) was administered on day 9. Blood, urine, feces, and saliva samples were collected at intervals throughout the study. Metabolite profiling was performed using radiochromatography, and metabolite identification was conducted using liquid chromatography-tandem mass spectrometry. The overall recovery of radioactivity was high (98.8%), with the majority recovered from feces (98.7%). There was minimal radioactivity in urine (0.113%) and saliva. Circulating radioactivity was predominantly confined to plasma with minimal partitioning into red blood cells. The terminal half-life of radioactivity in plasma was approximately 23 h with no evidence of any long-lasting metabolites. Faldaprevir was the predominant circulating form, accounting for 98 to 100% of plasma radioactivity from each subject. Faldaprevir was the only drug-related component detected in urine. Faldaprevir was also the major drug-related component in feces, representing 49.8% of the radioactive dose. The majority of the remainder of radioactivity in feces (41% of the dose) was accounted for in almost equal quantities by 2 hydroxylated metabolites. The most common adverse events were nausea, diarrhea, and constipation, all of which were related to study drug. In conclusion, faldaprevir is predominantly excreted in feces with negligible urinary excretion.

Disposition of S-1108, a new oral cephem antibiotic, and metabolic fate of pivalic acid liberated from [pivaloyl-14C]S-1108 in rats and dogs.

[pivaloyl-14C]S-1108, which is 14C labeled at the pivalic acid moiety of the pivaloyloxymethyl side chain of S-1108, was administered orally to rats and dogs, and the disposition of pivalic acid cleft from S-1108 was examined. Besides pivaloylcarnitine and pivaloylglucuronide, pivaloylglycine was identified in dog urine as a metabolite of pivalic acid by thin-layer chromatography and high-performance liquid chromatography analysis. The concentrations in the plasma of rats to which doses of 6.65, 26.6, and 532 mg/kg of body weight were administered showed dose-proportionate levels. The radioactivity was eliminated rapidly, with a half-life of approximately 3 h until 24 h at both the 6.65- and 26.6-mg/kg doses. Free pivalic acid in plasma accounted for more than 80% of the concentration of radioactivity. Radioactivity was distributed throughout the body and was eliminated quickly at a rate similar to that of radioactivity from plasma. Most of the absorbed radioactivity was excreted in the urine, and it was completed within 24 h after administration. In dogs, the half-life of radioactivity in plasma was longer than that in the rats. The ratio of free pivalic acid in plasma was 60 to 70% of the radioactivity in plasma. The concentration of radioactivity in the liver, cortex of the kidney, and skeletal muscle 144 h after oral dosing was more than 10 times higher than the concentration in plasma for all doses. Urinary excretion in dogs was slower than that in rats. The differences in the disposition of pivalic acid between dogs and rats may account for differences in the degree of skeletal muscle disorders. The safety in humans of S-1108 given at 200 mg three times a day is discussed in relation to the metabolic formation of the carnitine conjugate of pivalic acid and the reduction of the carnitine concentration in plasma.

Studies on Metabolic Fate of 14C-RU44570: Placental Transfer, Transfer into Milk, Absorption Site and Repeated Dosing in Rats, and Metabolism in Rats and Dogs.

The placental transfer, excretion into milk and site of absorption of 14C RU44570 were investigated in normal rats and male rats with ligated loops of gas trointestinal tract. The absorption, distribution, metabolism and excretion of 14C-RU44570 were examined during and after repeated oral administration to male rats at a daily dose of 1 mg/kg for 21 days. In addition, the metabolism of 14C-RU44570 in male dogs was studied after a single oral administration at a dose of 1 mg/kg. 1. In pregnant rats, receiving orally 1 mg/kg of 14C-RU44570 on the 18th days gestation, the level of radioactivity in fetus was lower than that in maternal plasma, and then ratio of the radioactivity was only 0.01% of the dose. In most of fetal tissues, the radioactivity levels decreased rapidly, however, relatively higher level was observed in the lung at 24 hr after the dosing. 2. The maximum concentration of radioactivity in the milk was found at 8 hr following oral administration of 14C-RU44570 at 1 mg/kg to lactating rats. The radioactivity concentration decreased with a half-life of 43 hr. 3. In a study of gastrointestinal absorption in situ, the most of 14C-RU44570 was found to be absorbed from duodenum and jejunum. 4. During repeated daily oral administration, plasma concentration of radioactivity at 24 hr did not increase significantly after the 7th dose. The elimination half-life of plasma radioactivity after the final dosing was comparable to that after the 1st dose. The radioactivity in most of tissues reached a steady state after the 7th or 14th dose during repeated administration. At 672 hr after the final dose, higher level of radioactivity was observed in the lung, while the concentration in other tissues decreased to lower level or even below the detection limit. 5. In plasma, urine, feces, bile or tissues, RU44403, which is a pharmacologically active form, was mainly found after both of single and repeated oral administration to male rats. Unchanged compound, RU44570, was not observed in plas ma and tissues. In addition, any conjugates of the metabolites were not found. 6. In plasma, urine or feces of male dogs, RU44403 was found as a major metabolite, however, RU44570 was also observed in dog plasma.

Metabolic disposition of the non-steroidal anti-inflammatory agent isoxicam in man.

The metabolic fate of isoxicam, a long half-life non-steroidal anti-inflammatory agent, in human subjects was investigated using isoxicam labelled with 14C in the N-methyl position. Three healthy male subjects were each administered a single oral 200 mg dose (90.7 microCi) with plasma and urine collected. Total plasma radioactivity peaked between 8 and 24 h postdose with mean 14C plasma radioactivity half-life of 36.1 h. Low levels of plasma radioactivity precluded plasma metabolic profiling. In urine, 37% of the administered radioactivity was recovered through 168 h. Metabolic profiling of urine confirmed the major oxidative excretion product as the hydroxymethylisoxazole metabolite. Identified and confirmed as minor urinary metabolites were radiolabelled open-ring sulfonamide and N-methylsaccharin. Non-labelled saccharin formed by oxidative loss of the 14C N-methyl group from N-methylsaccharin, was also observed. The role of this 'saccharin pathway' in the overall human disposition of isoxicam remains to be elucidated.

Absorption, distribution and excretion of lacidipine, a dihydropyridine calcium antagonist, in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog). 2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism. 3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug. 4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species. 5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses. 6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration. 7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.

Disposition of the aromatase inhibitor LY56110 and associated induction and inhibition studies in rats, dogs, and monkeys

Compound LY56110 was well absorbed but slowly excreted in the rat, dog, and monkey. Oral administration of 5 mg/kg of [ 14C]LY56110 (5-bis(4-chlorophenyl)methylpyrimidine) to the rat, monkey, and dog resulted in a total excretion of 68, 65, and 30% of the radioactivity within 5 days, respectively. Very low urinary excretion was observed in the rat and dog (2%), with fecal excretion being the predominant mode of elimination in all three species. The plasma radioactivity half-life was 49, 41, and greater than 100 hr in the rat, monkey, and dog, respectively. The plasma half-life of parent compound was 18 hr in the rat and 10 hr in the dog. LY56110 accounted for only 25, 12, and 1% of the plasma radioactivity area under the curve in the rat, dog, and monkey, respectively. High levels of radioactivity were observed in the target tissues of fat, adrenals, and ovaries of rats. LY56110 induced hepatic cytochromes b 5 and P-450 and cytochrome c reductase in rats after 14 days of oral dosing at 10 mg/kg but not in monkeys after 10 days of oral dosing at 10 mg/kg. The compound was more potent than aminoglutethimide or cimetidine in inhibiting hepatic ethylmorphine and p-nitroanisole demethylase activity in vitro. LY56110 also inhibited ethinamate-induced sleeping time in rats in vivo. The compound induced a reverse type I binding spectrum with rat ovarian microsomes.

Pharmacokinetics and Disposition of Carvedilol in Humans

Pharmacokinetics of carvedilol (C) have been studied in healthy volunteers after a single i.v. and oral administration, and the metabolic disposition after oral administration of 14C-labeled drug. C demonstrates dose-linear behavior. The absolute bioavailability reaches 24% probably due to a first-pass effect. After a 50 mg oral dose, maximum concentrations of 66 micrograms/l are achieved within 1.2 h. C is extensively distributed to the tissues (Vz = 132 l) and eliminated primarily by hepatic metabolism (total clearance 590 ml/min, renal clearance 4 ml/min). Because of the longer half-life of 6.4 h after oral administration in contrast to 2.4 h after i.v. administration, C is assumed to be absorption dependent since no sustained-release formulation was used. The half-life of radioactivity in plasma is 39 h; 16% of C is excreted in urine in the form of metabolites and only 0.3% unchanged. The urinary metabolites consist of carvedilol glucuronide (5.2% of the dose), cleavage products of the beta-blocking side chain (2.1%), and ring-hydroxylated forms (2.9%). Sixty percent of the dose is recovered in the feces. A demethylated product of C exhibits only minor beta-blocking activity. This metabolite is detected in plasma in concentrations ten times lower than the parent compound.

Pharmacokinetics and Disposition of Carvedilol in Humans

Summary: Pharmacokinetics of carvedilol (C) have been studied in healthy volunteers after a single i.v. and oral administration, and the metabolic disposition after oral administration of 14C-labeled drug. C demonstrates dose-linear behavior. The absolute bioavailability reaches 24% probably due to a first-pass effect. After a 50 mg oral dose, maximum concentrations of 66 μg/l are achieved within 1.2 h. C is extensively distributed to the tissues (Vz = 132 1) and eliminated primarily by hepatic metabolism (total clearance 590 ml/min, renal clearance 4 ml/min). Because of the longer half-life of 6.4 h after oral administration in contrast to 2.4 h after i.v. administration, C is assumed to be absorption dependent since no sustained-release formulation was used. The half-life of radioactivity in plasma is 39 h; 16% of C is excreted in urine in the form of metabolites and only 0.3% unchanged. The urinary metabolites consist of carvedilol glucuronide (5.2% of the dose), cleavage products of the β-blocking side chain (2.1%), and ring-hydroxylated forms (2.9%). Sixty percent of the dose is recovered in the feces. A demethylated product of C exhibits only minor β-blocking activity. This metabolite is detected in plasma in concentrations ten times lower than the parent compound.

Pharmacokinetics and Disposition of Carvedilol in Humans

Summary: Pharmacokinetics of carvedilol (C) have been studied in healthy volunteers after a single i.v. and oral administration, and the metabolic disposition after oral administration of 14C-labeled drug. C demonstrates dose-linear behavior. The absolute bioavailability reaches 24% probably due to a first-pass effect. After a 50 mg oral dose, maximum concentrations of 66 μg/l are achieved within 1.2 h. C is extensively distributed to the tissues (Vz = 132 1) and eliminated primarily by hepatic metabolism (total clearance 590 ml/min, renal clearance 4 ml/min). Because of the longer half-life of 6.4 h after oral administration in contrast to 2.4 h after i.v. administration, C is assumed to be absorption dependent since no sustained-release formulation was used. The half-life of radioactivity in plasma is 39 h; 16% of C is excreted in urine in the form of metabolites and only 0.3% unchanged. The urinary metabolites consist of carvedilol glucuronide (5.2% of the dose), cleavage products of the β-blocking side chain (2.1%), and ring-hydroxylated forms (2.9%). Sixty percent of the dose is recovered in the feces. A demethylated product of C exhibits only minor β-blocking activity. This metabolite is detected in plasma in concentrations ten times lower than the parent compound.

Antithrombin III: Biodistribution in Healthy Volunteers

Five healthy volunteers were injected intravenously with 73-90 uCi purified human 131I-Antithrombin III (AT III), specific biological activity 5.6 U/mg. The tracer data were analysed using a three compartment model. The plasma radioactivity half life was 66.2 +/- 1.2 (sem) h, the fractional catabolic rate constant of the plasma pool was 0.025 +/- 0.002 (sem) h-1. These data were comparable with those described in the literature. Because of the difficulty in translating the mathematical analysis of various compartments into the biological model, biodistribution was monitored by a gamma camera linked to a DEC PDP 11/34 computer system. Dynamic and static images were obtained at fixed time intervals following the injection of 131I-AT III. Whole body scanning at intervals between the time of injection (t = 0) and t = 24.5 h showed 131I-AT III distribution over the heart, lungs, liver, spleen and great vessels. Dynamic scanning was performed over the heart, spleen and liver. Overlayed frames in the first ten minutes after the 131I-AT III injection showed the following radioactivity expressed as percentage of the injected dose; 5.9% +/- 0.3 (sem) over the heart, 10.6% +/- 0.9 (sem) over the liver and 1.1% +/- 0.1 (sem) over the spleen. A slower decline of the radioactivity between t = 0 and t = 24 h; (19%) was measured over the liver compared with the radioactivity disappearance over the heart region. This shows, in combination with the fact that the radioactivity disappearance over the heart was identical with the radioactivity decline measured in the plasma samples that retention of 131I-AT III occurred in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of dibromodulcitol in humans: a phase I study.

A combined clinical and pharmacokinetic phase I study of the substituted hexitol dibromodulcitol (DBD), administered as a single oral monthly dose, has been performed. Twenty-three patients with advanced neoplasms received DBD doses ranging from 600 to 1,800 mg/m2 body surface area (BSA). The dose-limiting toxicity was myelosuppression, with both significant granulocytopenia and thrombocytopenia occurring at dose levels of 1,500 to 1,800 mg/m2. The average pharmacokinetic parameters for DBD, calculated on the basis of a one-compartment model with first-order absorption and elimination, include the elimination constant, .005 +/- .002/min; absorption constant, .012 +/- .009/min; and an apparent volume of distribution, 1.03 +/- .4 L/kg. The area under the drug concentration curve (AUC) and the peak drug level (Cmax) were linearly related to the dose administered (P less than .001). The mean AUC was 18.7 +/- 6.1 mmol/L min, and the mean Cmax was 47.1 +/- 16.8 mumol/L when normalized to a DBD dose of 1 gm/m2. The elimination constant was significantly reduced in patients with abnormal hepatic function (P less than .01). The elimination constant was not correlated with renal function. The half-life of DBD in plasma (158 minutes) was considerably shorter than the four-to eight-hour half-life of total radioactivity in plasma measured by previous investigators following the administration of radiolabeled DBD.

Turnover of human histidine-rich glycoprotein in healthy subjects and during thrombolytic therapy

Human histidine-rich glycoprotein, a protein with a potential antifibrinolytic effect, was purified to homogeneity and labeled with 125I. This material was injected intravenously and its turnover followed in 4 control subjects and in 3 patients undergoing thrombolytic therapy with streptokinase. The purified labeled histidine-rich glycoprotein behaved as a homogeneous protein in the turnover experiments and the plasma radioactivity disappearance rate could adequately be described by a sum of two exponential terms. The main metabolic parameters in the controls are : plasma radioactivity half-life 2.93 ± 0.36 days, fractional catabolic rate constant 0.51 ± 0.06 of the plasma pool per day, and synthetic rate 1.59 ± 0.35 mg7kg/day. During thrombolytic therapy with streptokinase the labeled histidine-rich glycoprotein disappeared with a half-life of only 1.43 ± 0.10 days due to an increased fractional catabolic rate constant (1.21 ± 0.13 of the plasma pool per day). At the same time the synthetic rate increased 2–3-fold (3.39 ± 2.35 mg/kg/day) resulting in only a slight decrease of the plasma level of histidine-rich glycoprotein.

Distribution of 14C-labelled 2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid, (indobufen or K 3920) in blood, platelets and platelet components.

The behaviour of 14C-labelled indobufen, an inhibitor of platelet aggregation, was examined and in 4 patients.The half-life of radioactivity in plasma was about 7 h, activity being mostly in cell-free plasma. Activity in platelets was never higher than the plasma level. When platelet fractions were examined, there was only a trace of activity in the sediment obtained by ultracentrifugation of disrupted platelets, and most of the platelet activity was found in cytosol. The half-life of activity was longest in cytosol and shortest in solid structures of platelets. From these results, the conclusion was drawn that indobufen does not bind irreversibly to platelets and that the activities found in platelets are a consequence of passive migration of the substance through the platelet membrane. These results also explain the shorter action of indobufen after a single dose in comparison with ASA which, in contrast, irreversibly binds to membrane proteins.

Turnover of Antiplasmin, the Fast-Acting Plasmin Inhibitor of Plasma

Human antiplasmin, the fast-acting plasmin inhibitor in plasma, was purified to homogeneity and labeled with 125I. This material, which was indistinguishable from antiplasmin in plasma with respect to several physicochemical and functional properties, was injected intravenously and its turnover measured in control subjects and in patients undergoing thrombolytic therapy. In eight control subjects (four healthy persons and four patients with atherosclerosis), the following turnover characteristics were obtained: plasma radioactivity half-life 2.64 +/- 0.32 days, fractional catabolic rate 0.53 +/- 0.09 of the plasma pool per day, intravascular fraction 0.51 +/- 0.05, and synthetic (catabolic) rate 1.4 +/- 0.27 mg/kg/day. The half-life of the plasmin-antiplasmin complex in plasma, measured from the disappearance rate of labeled antiplasmin, plasmin or plasmin-antiplasmin complex during thrombolytic therapy was approximately 0.5 days.

Turnover of antiplasmin, the fast-acting plasmin inhibitor of plasma

Human antiplasmin, the fast-acting plasmin inhibitor in plasma, was purified to homogeneity and labeled with 125I. This material, which was indistinguishable from antiplasmin in plasma with respect to several physicochemical and functional properties, was injected intravenously and its turnover measured in control subjects and in patients undergoing thrombolytic therapy. In eight control subjects (four healthy persons and four patients with atherosclerosis), the following turnover characteristics were obtained: plasma radioactivity half-life 2.64 +/- 0.32 days, fractional catabolic rate 0.53 +/- 0.09 of the plasma pool per day, intravascular fraction 0.51 +/- 0.05, and synthetic (catabolic) rate 1.4 +/- 0.27 mg/kg/day. The half-life of the plasmin-antiplasmin complex in plasma, measured from the disappearance rate of labeled antiplasmin, plasmin or plasmin-antiplasmin complex during thrombolytic therapy was approximately 0.5 days.

Inhibition of plasmin by antithrombin-heparin complex. II. During thrombolytic therapy in man.

The role of antithrombin as an inhibitor of plasmin in the presence and absence of heparin was studied during thrombolytic therapy in 12 patients with vascular occlusive disease. The extent of plasmin-antithrombin-(heparin) complex formation was studied by intravenous injection of iodine-labelled antithrombin (5-20 muCi) and quantitation of the amount of antithrombin bound to plasmin. In the absence of heparin, less than 0.8% of the labelled antithrombin was recovered in the plasmin-antithrombin complex but between 1.2 and 4.8% following injection of 5000 iu of heparin. Thus only between 3 and 11% of the in vivo formed plasmin is neutralized by antithrombin-heparin complex. Repeated activation of the fibrinolytic system resulted in a shortening of the plasma radioactivity half-life of labelled antithrombin from 2.45 to 2.03 d in the absence of heparin (three patients), and from 3.13 to 2.35 d following heparin administration (two patients). This increased turnover does not result in a decrease of the plasma antithrombin level.

Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration.

The metabolism of human antithrombin III (heparin cofactor) was studied in four control subjects, in four subjects with peripheral obliterative arterial disease, in six patients with recent venous thrombosis and in one patient with clinically severe haemophilia A. The labelled antithrombin III has a high specific activity (5.75 units/mg) and displayed a single band on SDS-polyacrylamide gel electrophoresis. On Sephadex G-100 gel filtration the labelled material eluted in the same position as the antithrombin III activity in plasma. Crossed immunoelectrophoresis of a mixture of fresh plasma and labelled antithrombin III against a specific antiserum, revealed a single precipitin line in which radioactivity was concentrated. The changes in electrophoretic mobility of both the plasma antithrombin III and the labelled material following the addition of heparin to the mixture or following coagulation were identical. The purified antithrombin III behaved as a homogeneous protein in the turnover experiments. The plasma radioactivity data were approximated by a sum of two exponential terms and the metabolism of antithrombin III represented by a two compartment mammillary model. Results in the control subjects were as follows: plasma antithrombin III concentration 19.6 +/- 2.3 mg/100 ml; intravascular fraction 0.45 +/- 0.05; fractional catabolic rate 0.55 +/- 0.02 of the plasma pool per day; half-life of the plasma radioactivity 2.83 +/- 0.26 days. Circulating large molecular weight degradation products of labelled antithrombin III could not be detected by Sephadex G-100 gel filtration. No significant differences in these parameters were found in the patients with peripheral arterial insufficiency. The turnover rate of antithrombin III was normal in the patient with haemophilia A. In three patients with venous thrombosis not treated with heparin, the turnover of labelled antithrombin III was in the normal range. In three patients with venous thrombosis, treated with heparin, the plasma radioactivity half-life was significantly shortened (2.13 +/- 0.08 days) and the fractional catabolic rate increased (0.75 +/- 0.05) of the plasma pool per day). In one of these patients, the labelled antithrombin III had been incubated with an equimolar amount of heparin prior to injection. In this patient the plasma radioactivity half-life was in the same range as in the other two patients (2.15 days).

Pharmacokinetics of glipizide in man: influence of renal insufficiency.

Four subjects received 5 mg14C-glipizide orally and3 subjects1 mg intravenously. The average absorption of the oral dose was nearly 100% with peak plasma levels occurring between 90 and 360 min. The apparent half-life of plasma radioactivity was approximatively 3.7 h, the disappearance of radioactivity following complex kinetics due to metabolism of the drug. Extraction with CH2Cl2 and chromatography showed that in plasma 85% of the total radioactivity corresponded to unchanged glipizide, but in urine 98% to more polar and more readily excreted metabolites. The urinary excretion is 68% of the dose. The hypoglycaemic effect of glipizide is comparable to glibenclamide. The administration of14C-glipizide to two patients with renal insufficiency showed that the metabolism of the drug is independent of kidney function, that the rate of disappearance of the unchanged glipizide was approximately the same as in normals, but that the “halflife” of the metabolites was increased to 20 h and more.

Metabolism of fibrinogen in cirrhosis of the liver.

The metabolism of human fibrinogen labeled with radioactive iodine was studied in 50 patients with documented cirrhosis of the liver and in 35 healthy control subjects. Results in cirrhotic subjects were the following: plasma volume 47 +/- 10 ml/kg; plasma fibrinogen concentration 250 +/- 102 mg/100 ml; total plasma fibrinogen pool 118 +/- 59 mg/kg, representing 0.73 +/- 0.10 of the total body pool; fibrinogen half-life 2.99 +/- 0.59 days; fractional catabolic rate 0.34 +/- 0.09 of the plasma pool per day; absolute catabolic rate 39 +/- 20 mg/kg per day; fractional transcapillary efflux rate 0.82 +/- 0.30 of the plasma pool per day. Results in the control subjects were the following: plasma volume 42 +/- 7 ml/kg; plasma fibrinogen concentration 284 +/- 71 mg/100 ml; total plasma fibrinogen pool 119 +/- 40 mg/kg, representing 0.72 +/- 0.07 of the total body pool; fibrinogen half-life 4.14 +/- 0.56 days; fractional catabolic rate 0.24 +/- 0.04 of the plasma pool per day; absolute catabolic rate 28 +/- 9 mg/kg per day; fractional transcapillary efflux rate 0.60 +/- 0.26 of the plasma pool per day.A significant difference between cirrhotics and controls was observed for plasma volume, fibrinogen half-life, fractional and total catabolic rates, and transcapillary efflux rate. During heparinization of 10 cirrhotic patients the fibrinogen half-life was prolonged from 3.15 +/- 0.69 to 4.59 +/- 0.79 days. This was associated with a rise in plasma fibrinogen in six out of eight patients. Heparinization did not influence the fibrinogen half-life in five control subjects. Inhibition of the fibrinolytic system in 17 patients resulted in prolongation of the plasma radioactivity half-life of more than 1 day in only three patients, an incidence comparable with that in five control subjects. These results strongly support the concept of accelerated fibrinogen consumption by a process of disseminated intravascular coagulation in cirrhosis of the liver.