4,4?-Dihydroxyphenazone as an urinary metabolite of phenazone in different species including man

Bässmann, H.; Böttcher, J.; Schüppel, R.

doi:10.1007/bf00501230

Cited by 23 publications

(2 citation statements)

References 9 publications

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“…Associated with the increase in antipyrine clearance after administration of rifapentine, there was an increase in the clearance to each of its three oxidative metabolites, although the change in CLHMA did not reach significance. Toverud et al (1981) (Bassmann et al, 1979). However, the results of the present study suggest that this pathway is not substantially increased by administration of rifapentine.…”

Section: Discussioncontrasting

confidence: 72%

Induction of mixed function oxidase activity in man by rifapentine (MDL 473), a long‐acting rifamycin derivative.

Durand¹,

Hampden²,

Boobis³

et al. 1986

Brit J Clinical Pharma

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The effects of rifapentine (MDL 473) administration on hepatic mixed function oxidase activity in man have been investigated in six healthy volunteers. Administration of rifapentine (600 mg 48 h‐1) for 10 days resulted in a significant reduction in antipyrine half‐life (from 13.2 +/‐ 1.0 h to 7.7 +/‐ 0.4 h) and a corresponding increase in its total body clearance (from 41.8 +/‐ 5.5 ml min‐1 to 67.4 +/‐ 5.6 ml min‐1). Twelve days after stopping rifapentine administration, these values had largely returned to base‐line. 24‐Hour excretion of 6 beta‐ hydroxycortisol was significantly increased, by approximately three‐ fold, following administration of rifapentine for 10 days. Again, 12 days after stopping drug administration, 6 beta‐hydroxycortisol excretion had returned to pretreatment values. Clearance of antipyrine to its three oxidative metabolites was increased by rifapentine administration, although the increase for 3‐hydroxymethylantipyrine was not significant. The greatest increase (+140%) was observed for norantipyrine. Twelve days after the last dose of rifapentine, all values had returned to control levels. It is concluded that, like rifampicin, rifapentine is a potent inducer of mixed function oxidase activity in man and that the possibility of clinically significant drug interactions should be anticipated in the therapeutic use of this compound.

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Section: Discussioncontrasting

confidence: 72%

Induction of mixed function oxidase activity in man by rifapentine (MDL 473), a long‐acting rifamycin derivative.

Durand¹,

Hampden²,

Boobis³

et al. 1986

Brit J Clinical Pharma

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“…It is of interest to note that between doses, mean total percentage excretion of OHA, NORA, HMA plus antipyrine remained without significant variation, between 79.0% and 80.7%. Aromatic ring hydroxylation of 4-hydroxyantipyrine, leading to the formation of 4,4'-dihydroxyantipyrine can account for 3-6 molar % of a dose of antipyrine in man (Bassmann et al, 1979). However, the results of the present study suggest that this pathway is not substantially increased by administration of rifapentine.…”

Section: Discussionmentioning

confidence: 99%

Untitled

1986

Brit J Clinical Pharma

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The effects of rifapentine (MDL 473) administration on hepatic mixed function oxidase activity in man have been investigated in six healthy volunteers. 2 Administration of rifapentine (600 mg 48 h7l) for 10 days resulted in a significant reduction in antipyrine half-life (from 13.2 + 1.0 h to 7.7 + 0.4 h) and a corresponding increase in its total body clearance (from 41.8 + 5.5 ml min-' to 67.4 ± 5.6 ml min-'). Twelve days after stopping rifapentine administration, these values had largely returned to base-line. 3 24-Hour excretion of 6p-hydroxycortisol was significantly increased, by approximately threefold , following administration of rifapentine for 10 days. Again, 12 days after stopping drug administration, 6p-hydroxycortisol excretion had returned to pretreatment values. 4 Clearance of antipyrine to its three oxidative metabolites was increased by rifapentine administration, although the increase for 3-hydroxymethylantipyrine was not significant. The greatest increase (+140%) was observed for norantipyrine. Twelve days after the last dose of rifapentine, all values had returned to control levels. 5 It is concluded that, like rifampicin, rifapentine is a potent inducer of mixed function oxidase activity in man and that the possibility of clinically significant drug interactions should be anticipated in the therapeutic use of this compound.

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Nifenazon, Biotransformation beim Menschen

Beyer

Friese

1985

Archiv der Pharmazie

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Die Biotransformation des Nifenazon beim Menschen wurde nach peroraler Gabe untersucht. Aus dem Urin wurden neben unverandertern Nifenazon vier noch nicht beschriebene Metabolite chromatographisch angereichert und isoliert. 4'-OH-Nifenazon, Nifenazon-N-oxid und NorNifenazon wurden durch 'H-NMR, IR und MS identifiziert, Nor-Nifenazon-N-oxid durch MS und Nor-Nifenazon-Glucuronid als TMS-Derivat charakterisiert. Das Vorkommen von 4-Aminophenazon als Metabolit konnte nicht bestatigt werden. Biotransformatioa of Nifenazoae in ManThe biotransformation of nifenazone in man after oral administration was examined. Besides unchanged nifenazone four new metabolites were enriched and isolated by chromatographic methods. The structures of rl'-OH-nifenazone, nifenazone-N-oxide and nor-nifenazone were identified by mass, 'H-NMR and IR spectroscopy. Indications for the presence of nor-nifenazone-N-oxide were obtained by the MS method. Nor-nifenazone glucuronide was identified by TMS derivatization. The occurrence of 4-aminophenazone as metabolite could not be confirmed.Die Pyrazolinon-Derivate Phenazon und Aminophenazon gehoren zu den altesten synthetisierten Pharmaka. Bereits 1934 wurde der Verdacht geaukrt, dal3 Aminophenazon Agranulocytosen'.') auslosen konnte. Diese Beobachtungen wurden von Plum'', RawLF4), Discombe5) und Hugulef') bestatigt. Aus Griinden der Arzneimittelsicherheit (Nebenwirkungen wie Blutbildveranderungen, anaphylaktische und andere allergische Reaktionen) wurde zum 1. Januar 1983 vom Bundesgesundheitsamt die Zulassung fiir alle Pyrazolinon-Derivate entweder geandert, zuriickgenommen oder der Anwendungsbereich eingeschrankt. Aminophenazon wurde bereits 1978 wegen des Verdachts der Kanzerogenitat in der BR Deutschland verboten. Die pathogenetischen Mechanismen der beschriebenen Nebenwirkungen sind bis jetzt noch nicht vollstandig bekannt. Fur ihre Aufklarung durfte unter anderem die genaue Kenntnis und der Vergleich der Biotransformation der einzelnen Pyrazolinone eine wesentliche Voraussetzung sein. In den letzten Jahren wurde der Metabolismus von Phenaz~n'**'~), Metamizol'o), Propyphenazon". und I~opyrin'~' eingehend untersucht. Fur ein weiteres Pyrazolinon, das antiphlogistische Analgetikum Nifenazon (4-Nicotinamido-2,3-dimethyl-l-phenyl-3-pyrazolin-5-on), liegen Untersuchungen aus dem Jahre 1964I4)vor. Danach wird Nifenazon beim Menschen zu 40-90 % unverandert und bis zu 0~6 5 -6~3 1~/ 0 9 0 9 -0~~~ s msom

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4,4?-Dihydroxyphenazone as an urinary metabolite of phenazone in different species including man

Cited by 23 publications

References 9 publications

Induction of mixed function oxidase activity in man by rifapentine (MDL 473), a long‐acting rifamycin derivative.

Induction of mixed function oxidase activity in man by rifapentine (MDL 473), a long‐acting rifamycin derivative.

Untitled

Nifenazon, Biotransformation beim Menschen

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