Metabolism of digitoxin in man and its modification by spironolactone

Summary The effect of spironolactone on the metabolism of intravenously administered³H-digitoxin (80 µCi) was investigated in eight patients. In three of them the labelled glycoside was given on a second occasion after spironolactone treatment had been discontinued for at least 65 days. Of total urinary radioactivity 79 % was unaltered drug and 12 % consisted of water soluble compounds. No digitoxigenin or digoxigenin and only trace amounts (<2 %) of digoxin and the bis- and monoglycosides of digoxigenin were found. After spironolactone total urinary radioactivity was unchanged but the fraction eliminated as unchanged digitoxin fell from 79 to 66 % and the water soluble compounds increased from 12 to 26 % (p<0.05). In addition spironolactone caused a 20 % reduction in the half-life of serum radioactivity (p<0.01) and a 16 % reduction in the volume of distribution (p<0.05). Induction of hepatic enzymes by spironolactone is proposed to explain the alteration in the metabolism of digitoxin in man. Both the altered metabolic pattern and the reduction in the volume of distribution appear to contribute to the reduction in half-life.Fellow of the Paul Martini-Stiftung, Frankfurt/Main, Germany     

Influence of spironolactone pretreatment on pharmacokinetics and metabolism of digitoxin in rats

Summary The influence of pretreatment with spironolactone (84 mg/kg at 3 days, twice per day) on the tritium levels in plasma, urine and feces of female SD-rats (n=9) was investigated at various time periods after oral administration of 25 g/kg ³H-digitoxin. In plasma, the concentrations of total radioactivity are reduced in pretreated animals to about 20% of tritium levels in control rats, while the half-life of radioactivity in both groups is almost identical, 2.9 days in pretreated rats and 2.8 days in controls. The lower plasma levels of tritium in pretreated rats coincide with a six-fold decrease in the urinary ³H-elimination and a corresponding increase in the fecal excretion. This is due to a higher biliary clearance of tritiated products in the early phase of elimination. The separation of the excretion products by TLC shows that spironolactone pretreatment enhances the splitting of the glycosidic bonds of digitoxin. The amount of digitoxigenin-bis-digitoxoside and of digitoxigenin-mono-digitoxoside excreted in urine and feces within 96 hrs is four and ten times greater than that recovered in control animals, respectively. The formation of the hydroxylation products digoxin and digoxigenin-bis-digitoxoside is decreased from 50% of the total excreted radioactivity in control to 15% in pretreated rats. The conjugation reactions with glucuronic and sulfuric acid are increased after pretreatment with spironolactone. Thus, the effect of spironolactone on digitoxin kinetics is apparently related to an enhancement of the hepatic excretory mechanism as well as to an enhanced metabolism.Supported by the Deutsche Forschungsgemeinschaft.     

Elimination of orally administered digoxin and digitoxin by thoracic duct drainage in man

Summary ³H-digoxin and³H-digitoxin were given orally to two middle-aged women who had thoracic duct lymphatic drainage. The plasma levels and urinary excretion of radioactivity were essentially the same as in normal controls. The cumulative recovery of³H-digoxin and its metabolites in lymph collected for 3 days was 4 per cent; and the corresponding value after administration of³H-digitoxin was 20 per cent. It was concluded that only minor amounts of digoxin and digitoxin are absorbed through lymphatic pathways.     

Different Effects of Microsomal Enzyme Inducers on the Biliary Excretion of Digoxin1

Abstract The effects of pretreatment with spironolactone, phenobarbital and 3,4–benzpyrene on biliary excretion of digoxin was studied in the isolated perfused rat liver system after a single dose of ³H–digoxin. After spironolactone pretreatment (100 mg/kg intraperitoneally for 4 days) the treated group excreted into bile in 45 min. 67 % of the administered dose compared to about 27 % in the control group. Since there was no significant increase in bile flow at any of the time periods, the enhanced biliary excretion of digoxin was entirely due to the increase in the bile level of digoxin or its metabolites or both. Pretreatment with phenobarbital (75 mg/kg intraperitoneally for 4 days) resulted in a slight increase in bile level of tritium at 15 min. and in bile flow, which could account for the doubled amount of digoxin excreted by the treated group, as compared to the control group at 45 min. Bile flow and biliary excretion of digoxin were unaffected by pretreatment with 3,4–benzpyrene (20 mg/kg intraperitoneally for 4 days). The results suggest that the enhancing effect of spironolactone and phenobarbital on biliary excretion of digoxin is a result of different mechanisms of action, which can not be directly related to the induction of microsomal drug metabolism.     

Changes in Steady State Digoxin Pharmacokinetics during Quinidine Therapy in Cardiac Patients: Influence of Plasma Quinidine Concentration

Abstract: In seven cardiac patients on long-term digoxin therapy, digoxin kinetics were investigated — in the absence and presence of quinidine — after simultaneous administration of an oral digoxin dose and an intravenous ³H-digoxin bolus injection. From ³H-digoxin data quinidine was found to decrease both renal (from 1.19 ±0.35 to 0.86 ±0.21 ml/min./kg) (P<0.02) and extrarenal clearances of digoxin (from 0.85 ±0.24 to 0.49±0.23 ml/min./kg) (P<0.02), and to diminish the steady state distribution volume of the drug (from 6.78 ± 1.23 to 5.63 ± 1.64 l/kg) (P<0.02). Plasma half-life increased from 51.5 ±5.4 to 64.4±14.8 hrs (P<0.05), while urinary excretion half-life increased from 54.4±3.9 to 78.5± 14.1 hrs (P<0.01). Pharmacokinetic parameters derived from plasma and urinary digoxin data showed similar changes during quinidine therapy. Reduction in renal ³H-digoxin clearance occurred at subtherapeutic plasma quinidine levels and was independent of plasma quinidine, whereas reductions in extrarenal ³H-digoxin clearance and ³H-digoxin distribution volume were positively correlated to plasma quinidine concentrations (P<0.05).     

Metabolism of Digoxigenin,digoxigeninmonodigitoxoside and digoxigeninbisdigitoxoside in rats

Summary The biliary and renal excretion products after i.d. administration of ³H-digoxigenin, ³H-digoxigenin-mono-digitoxoside and ³H-digoxigenin-bis-digitoxoside were studied in biliary fistula rats 65% and 58% of the given dose were excreted in bile and 10% and 5% in urine within 12 h after administration of mono-and-bis-glycoside respectively. Within 8 h, 45% and 4% of the given dose was eliminated in bile and urine after administration of digoxigenin.93–95% of the excreted radioactivity consisted of CHCl₃-soluble substances after administration of the bisglycoside, whereas the CHCl₃-soluble fraction accounted for only 30–45% of the biliary eliminated radioactivity after administration of the monoglycoside and the genin. The main excretion product after administration of bis-digitoxoside was the unchanged bisglycoside. After administration of monodigitoxoside, digitoxoside, the CHCl₃-soluble fraction in bile and urine was mainly represented by the monoglycoside and the 3-epigenin. Only traces of 3-ketogenin and no digoxigenin at all were detectable. The only CHCl₃-soluble excretion product in bile after administration of digoxigenin was its epimer, while in urine a few per cent of unchanged digoxigenin and 3-ketogenin could be identified.The CHCl₃-insoluble fraction after administration of bis- and-monodigitoxoside consisted of conjugation products with glucuronic and sulfuric acid. The monoglycoside was identified as the main conjugation partner after encymatic splitting of the polar fraction with -glucuronidase and sulfatase. Therefore the hydroxyl in C₃ of the steroid moiety cannot be conjugated preferentially with glucuronic or sulfuric acid during the metabolic decomposition of glycosides. This finding led to a degradation scheme of digoxin already discussed. Due to rapid metabolic inactivation of the monoglycoside to polar metabolites a therapeutic significance of this substance is very unlikely.     

Impaired biliary excretion of digitoxin and its metabolites after treatment with polychlorinated biphenyls.

In order to study the effects of polychlorinated biphenyls (PCB), potent inducers of microsomal drug-metabolizing enzymes, on the elimination rate of digitoxin (DT-3), the bile of rats were collected for 4 hr after a single dose of tritiated digitoxin ([³H]DT-3). In comparison to normal rats PCB caused a decrease of elimination by 50% whereas phenobarbital (PB) increased the rate by 36%. After extracting the bile with CHCl₃, measurements of radioactivity revealed that PCB-treated rats excreted only 3.2% of the dose as CHCl₃-soluble compounds. The corresponding fraction of both normal and PB-pretreated rats contained about 10% of the dose. The increased DT-3 elimination produced by PB was due to the large amount of water-soluble metabolites (nearly 24% of the dose). Normal and PCB-pretreated rats excreted about 10% water-soluble metabolites. Further analysis of metabolites showed: (1) In addition to the known metabolites (digoxin, bis-, and monodigitoxosides of both digitoxigenin and digoxigenin) the CHCl₃-soluble fraction contained a more lipophilic fraction. It consisted mainly of the dehydro-bis-digitoxoside of digitoxigenin. (2) Free genins could not be found. (3) Digitoxigenin monodigitoxoside was the main substrate for conjugating enzymes. (4) Nearly 30% of water-soluble metabolites were cardenolide acids presumably formed by hydrolysis of the butenolide. The results suggest that after PCB treatment the decreased DT-3 elimination rate is caused at least in part by an impaired digitoxoside cleavage.     

The effect of digoxin dosage on the digoxin-quinidine interaction in the bile duct-cannulated rat

Pretreating anaesthetized bile duct-cannulated rats with 9 mg kg-1 quinidine significantly decreased the cumulative biliary excretion of digoxin and its metabolites after 10 or 100 micrograms kg-1 [3H]digoxin, although the effect was more marked in animals receiving the high dose of digoxin. In contrast, however, although quinidine pretreatment raised plasma radioactivity levels by 50-80% in animals given the higher dose of digoxin, no significant effect on circulating plasma levels was observed in rats receiving 10 micrograms kg-1 digoxin. Generally, quinidine had no statistically significant effect on other aspects of digoxin disposition, although with both digoxin doses there were trends towards a reduction in the direct intestinal secretion and urinary excretion of digoxin-derived radioactivity with an increase in tissue levels of radioactivity (apart from the small intestine wall where concentrations were reduced). The radioactivity in the bile after 100 or 10 micrograms kg-1 digoxin comprised about 25 and 33% of digoxin and digoxigenin bis-digitoxoside, respectively, as well as appreciable amounts of the monodigitoxoside and a highly polar component. This metabolite profile was unaffected by quinidine. The influence of cardiac glycoside dosage shown by the present work indicates that the digoxin-quinidine interaction and possibly analogous interactions involving other cardiac glycosides, may not always be readily detectable from plasma concentration data.     

Pharmacokinetics and metabolism of digoxigenin-mono-digitoxoside in man

Summary ³H-digoxigenin-mono-digitoxoside 1 mg was swallowed by 6 healthy subjects. Maximum plasma levels of radioactivity were reached within 1–2 h; in two subjects there was a second peak at 8–12 h. No definite half lives could be determined because the falls in plasma activity were not exponential. 3.9–39% and 34.5–76.6% of the dose were eliminated in urine and faeces, respectively. 75–90% of the total radioactivity in plasma was CHCl₃-insoluble, there was less of this fraction in urine, and the major portion in faceces was CHCl₃-soluble. The CHCl₃-insoluble fraction in urine was separated into 3 components by chromatography on an Al₂O₃-column and consisted mainly of conjugates of the monoglycoside and 3-epidigoxigenin. TLC-separation of the lipophilic fraction in urine also revealed unchanged monoglycoside and 3-epidigoxigenin, as well as traces of digoxigenin, 3-ketodigoxigenin and 2 unidentified, more polar metabolites. In faeces, the main excretion product was the unchanged compound, and traces of digoxigenin, 3-epidigoxigenin, 3-ketodigoxigenin and one of the more polar metabolites detected in urine. Two patients with surgical T-tube bile-duct drainage showed significantly greater biliary excretion after oral administration of the digoxigenin-mono-digitoxoside than after digoxin. Almost all the radioactivity excreted in bile was CHCl₃-insoluble and the monoglycoside was shown to be the only conjugation partner present by incubation with arylsulfatase and -glucuronidase. The results show that digoxigenin-mono-digitoxoside has such a rapid metabolic inactivation and biliary clearance in man that it is unlikely to be of any therapeutic value.This study was supported by the Deutsche Forschungsgemeinschaft.     

Pharmacokinetics of digoxin and main metabolites/derivatives in healthy humans

Three healthy, young male volunteers received doses of 0.6 and 1.2 mg of specifically labelled [3H]digoxin each by intravenous (i.v.) bolus injection and oral (p.o.) administration in accordance with a randomized four-way crossover design. Plasma, urine, and feces samples were taken over an interval of 144 h after drug administration. Total radioactivity and individual radioactivity assignable to digoxin and its metabolites were measured. After i.v. administration, the mean +/- SD recovery of total radioactivity, as percent of dose, was complete, urine 81.3 +/- 2.0% and feces 17.1 +/- 2.8%. The mean recovery of digoxin and that of its metabolites in urine was digoxin 75.6 +/- 3.0%, dihydrodigoxin 2.8 +/- 1.6%, digoxigenin bisdigitoxoside 1.6 +/- 0.1%, and additional metabolites 1.5 +/- 0.3%. Judging from the metabolite data in urine and considering the 5% impurity of the administered dose, metabolism of digoxin appeared to be insignificant after i.v. administration. The total and renal clearances of digoxin were, on average, 193 +/- 25 ml min-1 and 152 +/- 24 ml min-1. The mean steady state volume of distribution was 489 +/- 73 L and the mean residence time 41 +/- 5 h. For the metabolites dihydrodigoxin and digoxigenin bisdigitoxoside the mean residence times were on average 35 +/- 9 h and 53 +/- 11 h; the renal clearances were 79 +/- 13 ml min-1 and 100 +/- 26 ml min-1. After p.o. administration, the mean recovery of total radioactivity, as percent of the dose, was also complete, urine 65.7 +/- 1.98% and feces 31.6 +/- 7.6%. The mean recovery of digoxin and that of its metabolites, as percent of dose, in urine was digoxin 51.5 +/- 11.4%, dihydrodigoxin 4.5 +/- 3.9%, digoxigenin bisdigitoxoside 1.9 +/- 0.1%, polar metabolites 5.5 +/- 3.8%, and additional metabolites 1.3 +/- 0.6%. After p.o., as compared to i.v. administration, larger amounts of all the metabolites were formed in accordance with first pass metabolism/degradation. Maximum mean plasma concentrations of 4.3 +/- 2.5 ng ml-1 and 9.5 +/- 1.1 ng ml-1 for digoxin were observed at 40 +/- 10 min after p.o. administration of 0.6 and 1.2 mg of the drug. The mean absolute bioavailability of digoxin from an aqueous solution was 0.67 +/- 0.14. Renal clearance and mean oral residence time for digoxin were on average 176 +/- 28 ml min-1 and 37 +/- 4 h after p.o. administration.(ABSTRACT TRUNCATED AT 400 WORDS)     

Excretion of [3H]triptolide and its metabolites in rats after oral administration

Aim： To investigate the routes of elimination and excretion for triptolide recovered in rats.
Methods： After a single oral administration of [3H]triptolide （0.8 mg/kg, 100 μCi/kg） in Sprague Dawley rats, urine and fecal samples were collected for 168 h. To study biliary excretion, bile samples were collected for 24 h through bile duct cannulation. Radioactivity was measured using a liquid scintillation analyzer, and excretion pathway analysis was performed using an HPLC/on-line radioactivity detector.

Results： The total radioactivity recovered from the urine and feces of rats without bile duct ligation ranged from 86.6%–89.1%. Most of the radioactivity （68.6%–72.0%） was recovered in the feces within 72 h after oral administration, while the radioactivity recovered in the urine and bile was 17.1%–18.0% and 39.0%–39.4%, respectively. The HPLC/on-line radiochromatographic analysis revealed that most of the drug-related radioactivity was in the form of metabolites. In addition, significant gender differences in the quantity of these metabolites were found： monohydroxytriptolide sulfates were the major metabolites detected in the urine, feces, and bile of female rats, while only traces of these metabolites were found in male rats.

Conclusion： Radiolabeled triptolide is mainly secreted in bile and eliminated in feces. The absorbed radioactivity is primarily eliminated in the form of metabolites, and significant gender differences are observed in the quantity of recovered metabolites, which are likely caused by the gender-specific expression of sulfotransferases.     

Studies on the mechanism of spironolactone protection against indomethacin toxicity

Pretreatment of rats for 4 days with spironolactone (75 mg/kg) increases the LD50 of indomethacin from 13 (12.7–14.5) mg/kg ip to 37 (34–41) mg/kg ip. In an attempt to determine the mechanism by which spironolactone decreases the toxicity of indomethacin, [¹⁴C]indomethacin (8 mg/kg) was administered ip to control and spironolactone-pretreated rats and the concentration of ¹⁴C in various tissues was determined at timed intervals up to 4 hr. The concentration of ¹⁴C in the tissues of the two groups 30 and 60 min after [¹⁴C]indomethacin administration were similar, but at the 2-, 3-, and 4-hr time intervals, the concentration of ¹⁴C was lower in the blood, plasma, lung, heart, spleen, and muscle of the spironolactone-pretreated rats. This indicates that spironolactone enhances the excretion of indomethacin. The mechanism of the enhanced excretion was studied using [¹⁴C]indomethacin administered iv (4 mg/kg) to control and spironolactone-pretreated rats. The amount of ¹⁴C in the plasma and bile was measured. Spironolactone markedly enhanced the plasma disappearance of ¹⁴C and more than doubled the rate of its excretion into the bile. The increased excretion of ¹⁴C into the bile of the spironolactone-pretreated rats was mostly in the form of more water-soluble metabolites. The increased plasma disappearance and biliary excretion of indomethacin is also observed after other microsomal enzyme inducers. Phenobarbital (75 mg/kg) and pregnenolone-16α-carbonitrile (75 mg/kg) produced a similar increase in the plasma disappearance and biliary excretion of indomethacin as did spironolactone, but 3-methylcholanthrene (20 mg/kg) was without effect. Thus, it appears that spironolactone decreases the toxicity of indomethacin by increasing its biotransformation and excretion into the bile.     

Disposition kinetics of spironolactone in hepatic failure after single doses and prolonged treatment

Summary Six male patients with histologically characterised, decompensated liver disease who had not previously received spironolactone, were given orally Aldactone^® 7 mg/kg with³H-spironolactone 100 µCi. The kinetics of the drug were studied in plasma and urine for 6 days. Then, Aldactone^® 7 mg/kg was given daily for 12 consecutive days, and the pharmacokinetics of a single dose of³H-spironolactone were re-examined. The kinetics of total radioactivity, as well as of fluorigenic metabolites in plasma, after the first single dose of spironolactone did not differ in patients and normal test subjects; similar percentages of the dose given were excreted within 6 days in urine from patients (47.47±4.88%) and from controls (53.68±2.04%). The kinetics of CH₂Cl₂/H₂O distribution coefficients of labelled material in plasma and urine, as well as TLC analysis of the CH₂Cl₂ soluble fraction, revealed no significant differences from controls. After treatment for 12 days with spironolactone, 4 out of 6 patients showed marked acceleration in the rate of elimination of radioactivity from plasma and a corresponding increase in excretion of labelled compounds in urine. Analysis of the excretion products in urine revealed proportionally increased excretion and no evidence of selective induction of a single degradation step. In contrast, delayed elimination was observed in the 2 other patients after 12 days' treatment. However, this was due to dehydration and oliguria caused by over-treatment with the diuretic.     

Absorption,distribution, metabolism and excretion of gemigliptin,a novel dipeptidyl peptidase IV inhibitor,in rats

Abstract

1.?The absorption, distribution, metabolism and excretion of a novel dipeptidyl peptidase IV inhibitor, gemigliptin, were examined following single oral administration of ¹⁴C-labeled gemigliptin to rats.

2.?The ¹⁴C-labeled gemigliptin was rapidly absorbed after oral administration, and its bioavailability was 95.2% (by total radioactivity). Distribution to specific tissues other than the digestive organs was not observed. Within 7 days after oral administration, 43.6% of the administered dose was excreted via urine and 41.2% was excreted via feces. Biliary excretion of the radioactivity was about 17.7% for the first 24?h. After oral administration of gemigliptin to rats, the in vivo metabolism of gemigliptin was investigated with bile, urine, feces, plasma and liver samples.

3.?The major metabolic pathway was hydroxylation, and the major circulating metabolites were a dehydrated metabolite (LC15-0516) and hydroxylated metabolites (LC15-0635 and LC15-0636).     

Metabolism and excretion of 3H-digitoxin in the rat

After oral administration of 25 μg/kg ³H-labelled digitoxin (sp. act. 26.2 mCi/mg) to female rats, the total radioactivity in blood and in urine was eliminated with a half-life time of 2 and 1.7 days, respectively. The fecal elimination half-life time had a. biphasic course. The chloroform-soluble and chloroform-insoluble metabolites excreted in urine and feces were determined in order to explain the much shorter half-life time of 0.4 days in feces during the early phase of elimination. In the feces, 45 per cent of the dose excreted within 5 days consisted of chloroform-soluble substances. In this fraction, the main excretion product was digoxigenin-bis-digitoxoside (20 per cent), whereas the percentages of the other glycosides, after the last collection period, amounted to significantly less: 9% digitoxin, 9% digoxin. 5% digitoxigenin-bis-digitoxoside, and 2% digitoxigenin-mono-digitoxoside. The Chromatographic analysis of the chloroform-insoluble fraction, which accounted for 15 per cent of the dose. revealed a conjugation of glucuronic and sulfuric acid with digoxin, and digoxin, 5% digitoxigenin-bis-digitoxosidc. and 2% digitoxigenin-mono-digitoxoside. The contrast, sulfuric acid alone was the main conjugation partner of 3-epi-digitoxigenin. In urine, 4.6 per cent of the administered radioactivity was represented by digoxin, 2 per cent by digitoxin, 1 per cent by digoxigenin-bis-digitoxoside, and 1.4 per cent by polar metabolites. Only traces of digitoxigenin-bis-digitoxoside cind digoxigenin-mono-digitoxoside were detected. The much shorter half-life time of the eliminated radioactivity in feces seems to be due to the higher portion of poorly reabsorbed conjugation products and digoxigeninbis-digitoxoside.     

Metabolism is an Important Route of Pentamidine Elimination in the Rat: Disposition of 14C-Pentamidine and Identification of Metabolites in Urine Using Liquid Chromatography-Tandem Mass Spectrometry

Abstract: This study assesses the contribution of metabolism for the disposition of pentamidine in the rat. With the use of ¹⁴C-labelled compound, the excretion of radioactivity in urine and faeces has been studied in four rats during 44 days after a single intravenous injection of the drug. The urinary and faecal excretion of the radioactivity were of equal importance; 22±2% (mean±S.D.) and 25±4% being detected in urine and faeces, respectively. The activity in organs and tissues at 44 days after drug administration was also measured and amounted to 21±5% of the administered dose. Using HPLC the proportion of metabolites in urine in relation to unchanged pentamidine increased with time after dose, being 76±15% (mean±S.D.) of the total excreted radioactivity on day 1 and 97±1% on day 6. HPLC - tandem mass spectrometry was used for identification of metabolites in urine obtained from four rats given unlabelled pentamidine. Using synthetic reference compounds and the selective MS/MS mode four oxidized metabolites of pentamidine were identified either by direct injection into the system or by analyses of extracted urine. Thus, a substantial part of pentamidine is excreted as metabolites in urine.     

Absorption,metabolism and excretion of cobimetinib,an oral MEK inhibitor,in rats and dogs

1.?The absorption, metabolism and excretion of cobimetinib, an allosteric inhibitor of MEK1/2, was characterized in mass balance studies following single oral administration of radiolabeled (¹⁴C) cobimetinib to Sprague–Dawley rats (30?mg/kg) and Beagle dogs (5?mg/kg).

2.?The oral dose of cobimetinib was well absorbed (81% and 71% in rats and dogs, respectively). The maximal plasma concentrations for cobimetinib and total radioactivity were reached at 2–3?h post-dose. Drug-derived radioactivity was fully recovered (～90% of the administered dose) with the majority eliminated in feces via biliary excretion (78% of the dose for rats and 65% for dogs). The recoveries were nearly complete after the first 48?h following dosing.

3.?The metabolic profiles indicated extensive metabolism of cobimetinib prior to its elimination. For rats, the predominant metabolic pathway was hydroxylation at the aromatic core. Lower exposures for cobimetinib and total radioactivity were observed in male rats compared with female rats, which was consistent to in vitro higher clearance of cobimetinib for male rats. For dogs, sequential oxidative reactions occurred at the aliphatic portion of the molecule. Though rat metabolism was well-predicted in vitro with liver microsomes, dog metabolism was not.

4.?Rats and dogs were exposed to the two major human circulating Phase II metabolites, which provided relevant metabolite safety assessment. In general, the extensive sequential oxidative metabolism in dogs, and not the aromatic hydroxylation in rats, was more indicative of the metabolism of cobimetinib in humans.     

Pharmacodynamics,pharmacokinetics and metabolism of digitoxin and derivatives in cats

Summary Derivatives of dihydro-digitoxin (DHD) were studied in the search for a glycoside with a primarily extra-renal clearance and a faster elimination rate than digitoxin. The positive inotropic doses of the derivatives of DHD were higher than those of digitoxin and digoxin. There was no significant difference in the therapeutic margin. After injection of ³H-digoxin in unaesthetized cats, no metabolites were found in the serum which did not bind with the antibody used for the RIA. After injection of ³H-digitoxin, and its derivatives, the radioactivity was cleared from the serum at a much lower rate than the concentrations assayed by RIA. The metabolites which did not bind to the digitoxin antibody were hydrophilic and had a low protein binding. Digitoxin-bisdigitoxoside (Dt-2) determined by RIA rapidly disappeared from the serum. The radioactivity remaining after 24 h was eliminated with a half-life of 219 h. Ten min after injection of DHD the serum contained no unchanged DHD, but 36% digitoxin suggesting that the reduction of digitoxin to DHD is reversible and that the conversion of DHD to Dt-2 is the rate limiting step in the metabolism of digitoxin. The total body clearance of digitoxin, its metabolites and derivatives determined by RIA increased in the order DHD-oxime digitoxin > DHD DHD-acetyloxime < DHD-methyloxime. The clearance and the elimination rate of DHD-methyloxime were significantly higher than those of digitoxin (P = 0.05). Send offprint requests to W. Schaumann at the above address     

Excretion of digoxin and its metabolites in urine after a single oral dose in healthy subjects

The 3-day urinary excretion of digoxin, its conjugated and unconjugated hydrolytic metabolites and dihydrodigoxin, was studied in 8 healthy men after oral administration of tritiated digoxin. Analysis was performed by high pressure liquid chromatography (HPLC). The total radioactivity corresponded to 45.4±2.0 per cent (mean ± S.E.M.) of the dose. By HPLC 424 ± 2.7 per cent was recovered before and 44.0 ± 2.7 per cent after deconjugation of the samples. Digoxin and dihydrodigoxin constituted 40.3 ± 2.9 per cent; of this 0.7 ± 0.4 per cent was dihydrodigoxin. The sum of the hydrolytic metabolites was 2.1 ± 0.3 per cent before and 3.4± 0.5 per cent after deconjugation. No correlation was found between gastric pH and the production of hydrolytic metabolites. The relative amount of these metabolites was maximal (mean 13.4 per cent of the excretion) in the 4.8 h sampling period. During the first 8 h an average of 8.6 per cent of the radioactivity was not recovered by HPLC. The metabolism of digoxin as judged by urinary excretion was limited and showed great variation during the early hours after treatment. The excretion of unchanged digoxin in some individuals constituted as little as 60 per cent over the first 12 h after dosing.     

Disposition and metabolism of amosulalol hydrochloride,a new combined α- and β-adrenoceptor blocking agent,in rats,dogs and monkeys

1. The disposition and metabolism of amosulalol hydrochloride, a combined α- and β-adrenoceptor blocking agent, were studied in rats, dogs and monkeys.

2. After oral administration of [¹⁴C]amosulalol hydrochloride, the plasma concentration of radioactivity reached a maximum at 05 to 1 h in all species and declined with half-lives of about 2 h in both rats and monkeys, and of about 4 h in dogs. The ratios of unchanged drug to total radioactivity in the rat and dog plasma were 8 and 43% at 05 h after administration, respectively. The radioactivity in the rat tissues was high in the liver, kidney, blood and pancreas after oral administration.

3. Following oral dosage, the urinary excretion of radioactivity was 26-34% of the dose in rats, 45% in dogs and 46% in monkeys in 48 h. The biliary excretion after oral dosage amounted to 66% and 41% in rats and dogs, respectively.

4. Six metabolites were isolated and identified from the urine of rats and dogs. They were derived from one or two of the following pathways: I, hydroxylation of the 2-methyl group of the methylbenzenesulphonamide ring; II, demethylation of the o-methoxy group of the methoxyphenoxy ring; III, hydroxylation at the 4 or 5 position of the methoxy-phenoxy ring; IV, oxidative cleavage of the C—N bond yielding o-methoxyphenoxy acetic acid. Moreover, some metabolites were metabolized to glucuronide or sulphate.