Biotransformation and pharmacokinetics of acenocoumarol (Sintrom�) in man

Dieterle, W.; Faigle, J. W.; Montigel, C; Šulc, Miloslav; Theobald, W

doi:10.1007/bf00566534

Cited by 49 publications

(28 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Plasma levels of AM exceeded those of AC from beyond 2 h in one subject and from beyond 10 h in the other. Urinary excretion of both the metabolites accounted for 20-30% of the AC dose (Dieterle et al, 1977). Our experiments show complete opposite results.…”

Section: Resultscontrasting

confidence: 66%

“…The prime objective of the present study was to investigate the relevance of the potential AC metabolites, AM and AA, for the anticoagulant activity of the former. Dieterle et al (1977) showed for two subjects that upon oral administration, AC was extensively metabolized, mainly by reduction to AM and subsequent acetylation to AA. Plasma levels of AM exceeded those of AC from beyond 2 h in one subject and from beyond 10 h in the other.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?

Thijssen¹,

Baars²

1983

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 The pharmacokinetics and pharmacodynamics of racemic acenocoumarol (AC), the amino (AM) and acetamido (AA) derivative were investigated in healthy volunteers after administration of a single oral (10 mg) dose. 2 All three coumarins were rapidly absorbed from the gastrointestinal tract. The elimination half-lives were 10.9, 10.4, and 4.1 h, for AC, AM and AA, respectively. 3 After the oral administration of AC, no AM and AA was detected in the plasma, and less than 1% of the dose was recovered in the urine (0-24 h) as AM. 4 Renal clearance was the main route of elimination of AM and AA; the former by glomerular filtration, the latter by active excretion. 5 Binding to serum proteins was the highest for AC (1.52% free). AM and AA were less tightly bound (about 3% free). AM or AA did not interfere with the AC plasma protein binding. 6 The oral administration of AC resulted in a rise in prothrombin time with a maximum effect at 24 to 30 h. No anticoagulant activity was observed upon the administration of AM and AA. 7 The results indicate that the compounds AM and AA, if they are formed out of AC at all, do not contribute to the anticoagulant activity of AC.

show abstract

Section: Resultscontrasting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?

Thijssen¹,

Baars²

1983

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…The 7-hydroxy-metabolite proved to be inactive in mice, but the other metabolites induced a greater and longer-lasting depression of the prothrombin level than acenocoumarol (Dieterle et al, 1977).…”

Section: Studymentioning

confidence: 90%

“…Since acenocoumarol is eliminated almost entirely by hepatic metabolism (Dieterle et al, 1977), the total plasma clearance mainly reflects the metabolic clearance of this drug. The apparent elimination half-life (T,2) of the racemate (Table 1) is similar to the values already reported after oral administration of 12 mg of 14C-labelled racemate: 8.7 and 8.2 h for the two subjects (Dieterle et al, 1977). The apparent volumes of distribution of the two enantiomers differed by a factor of 1.5 to 2 (Table 1).…”

Section: Studymentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics of the enantiomers of acenocoumarol in man.

Godbillon¹,

Richard²,

Gérardin³

et al. 1981

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 The pharmacokinetics of R(+)-, S(-)-and R,S(+)-acenocoumarol were studied in healthy volunteers after administration of single oral and intravenous doses. 2 After both oral and i.v. administration of either enantiomer in a dose of 0.25 mg/kg, the concentrations of R(+) found in the plasma were much higher than those of S(-). This indicates that the observed differences are not related to stereoselective absorption. 3 After intravenous administration of 25 mg of each enantiomer and the racemate, the total plasma clearance of S(-) was about 10 times that of R(+). The clearance of the racemate was between that of the enantiomers. 4 The apparent elimination half-life of S(-) was much shorter than those of R(+) and the racemate, which were similar. 5 The apparent volume ofdistribution Vdss of S(-) acenocoumarol was 1.5 to 2 times that of R(+). 6 Measurements of the extent of binding to serum proteins, made in vitro at much higher concentrations than those observed in vivo, revealed no differences between the two enantiomers and the racemate. 7 The results indicate that the greater anticoagulant potency of R(+) compared with S(-) acenocoumarol can be explained mainly by stereoselective differences in their metabolic clearance.

show abstract

Investigation of the Protein Binding of Drugs by Continuous Ultrafiltration, vi: Protein Binding of Acenocoumarol

Rehse

Ehlert

1985

Archiv der Pharmazie

View full text Add to dashboard Cite

In mehreren Mitt. haben wir uber die Validitat der kontinuierlichen Ultrafiltration zur raschen und sicheren Bestimmung von Proteinbindungsparametern berichtet. Voraussetzung fiir die Anwendbarkeit der Methode auf hochgradig an Protein gebundene Substanzen ist die Vefigbarkeit einer Detektionsmethode, die es gestattet, den Arzneistoff im DurchfluRverfahren in Konzentrationen zu messen, die zwei bis drei GroRenordnungen unter seinem Plasmaspiegel liegen. Im Gegensatz zu anderen Anticoagulantien vom 4-Hydroxycumarintyp zeigt Acenocoumarol (Sintrom') keine Fluoreszenz. Dies hatte zur Folge, daB seine EiweiBbindung bisher nur diskontinuierlich unter Verwendung radioaktiv markierten Materials14) oder fur unphysiologisch niedrige Proteinkonzen-trationen5r6) respektive kontinuierlich in unphysiologisch hohen Substanzkonzentrationen') durch UV-Detektion bestimmt werden konnte.Es lassen sich jedoch reproduzierbare Bestimmungen im UV-Bereich bis zu Konzentrationen von cf = 10nmolll entsprechend 2,5 bis 5 Milliextinktionen durchfiihren, wenn ein empfindlicher und stabiler Detektor vorhanden ist . Die DurchfluBkuvette des UV-Detektors mu13 bei diesen Messungen exakt thermostatisiert werden. Aus dem unter derartigen Bedingungen von uns erhaltenen kontinuierlichen Satz von MeBergebnissen sind die Werte fiir einige Konzentrationen herausgegriffen und in Tab. 1 zusammengefdt worden. Man erkennt, daB a im Bereich von 2,5-10pmoM praktisch konstant und etwa doppelt so groB wie bei Warfarin ist. Hieraus extrapolieren wir, daB auch im therapeutisch genutzten Konzentrationsbereich um ctot = 1 pmoYl') ahnliche Bindungsverhaltnisse vorliegen werden. Die Konzentration an ungebundenem Acenocoumarol steigt wegen c,= a-c,,,,.iiber den MeRbereich linear an. Der bei eins liegende Wert der Tab. 1: Proteinbindungsparameter von Acenocoumarol ctot [PmolllI kl. 104 Il/moll K* 2.5 5.0 7.5 10.0 Scatchard Scholtun [rmol/l] m OL 0.52 0.55 0.57 0.58 30.9 32.0 141.9 0.90 Srel [%] 12.9 11.5 19.5 11.7 12.8 10.7 41.7 18.0 0365-6233/85/0606-0573 5 M.SO/O OVCH Verlagsgesellschaft mhH. D-6940 Weinheim, 1985

show abstract

Biotransformation and pharmacokinetics of acenocoumarol (Sintrom�) in man

Cited by 49 publications

References 18 publications

Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?

Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?

Pharmacokinetics of the enantiomers of acenocoumarol in man.

Investigation of the Protein Binding of Drugs by Continuous Ultrafiltration, vi: Protein Binding of Acenocoumarol

Contact Info

Product

Resources

About