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Kinetics and Metabolism of Pyrazolones (Propyphenazone, Aminopyrine and Dipyrone)

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Kinetics and Metabolism of Pyrazolones (Propyphenazone, Aminopyrine and Dipyrone) Br. J. clin. Pharmac. (1980), 10, 299S-308S KINETICS AND METABOLISM OF PYRAZOLONES (PROPYPHENAZONE, AMINOPYRINE AND DIPYRONE) MANFRED VOLZ & HANS-MARTIN KELLNER Hoechst AG, Postfach 80 03 20, 6230 Frankfurt am Main 80, West Germany 1 Propyphenazone 220 mg was administered orally to volunteers. Maximum plasma concentra- tions between 1.5 ,ug/ml and 3.5 Hg/ml were found 30 min later. After comparable doses plasma concentrations in dog and rabbit were lower. The distribution volumes were 2 1/kg. 2 The major metabolic route of propyphenazone is demethylation. The main urinary metabolite is the enolglucuronide of N-(2)-demethylpropyphenazone. 3 Aminopyrine is rapidly and almost completely absorbed after oral administration. Maximum plasma concentrations of 10 .g/ml are reached 1.5 h after a 500 mg dose. The biological half-life is 2-3 h, the relative distribution volume 6007 on average, and binding to plasma proteins approxi- mately 15%. 4 Unchanged aminopyrine is only excreted in small quantities. The major routes of metabolism are demethylation (4-methylaminoantipyrine and 4-aminoantipyrine) and acylation (4-acetyl and 4-formylaminoantipyrine). There are other biotransformation products. 5 After oral administration of [14C]-dipyrone 480 mg the maximum serum concentration of 13.4±0.8 ,ug/ml occurred at 1-1.5 hours. 6 Dipyrone was not detectable in serum or urine. Four of seven metabolites were identified, and were identical with the main metabolites of aminopyrine. Introduction THE pyrazolones are among the oldest synthetic Using this method, maximum propyphenazone pharmaceuticals. Knorr first prepared antipyrine in concentrations of 1.5-3.5 ,g/ml can be expected in 1883. Figure 1 represents the basic structure from the plasma after an oral dose of 220 mg and which other pharmacologically important pyrazo- maximum concentrations of 3.5-12.5iAg/ml after lones are derived by substitution on the C-4 440 mg. The maximum levels were reached 0.5-0.6 h atom. after dosing (Ciba Geigy AG, 1979, unpublished In the search for derivatives with a greater thera- data). peutic activity the hydrogen on C4 of antipyrine was Dell & Kolle (1978) reported a thin layer chroma- first substituted by the isopropyl radical to give tographic method, by which they were able to detect propyphenazone. This has improved antipyretic and propyphenazone in the blood up to 10 h after an oral analgesic properties and exhibits anti-inflammatory dose of 240 mg in man. activity. After propyphenazone (150 mg/kg orally) in rabbits (Figure 2), a maximum of 42 Ag/ml has been Propyphenazone found (Naito, 1963) 2 h after adminstration with a mean biological half-life of approximately 2.8+0.6 h. There are few published reports about the plasma In dog (Dell et al., 1978) and in rabbit (Naito, concentrations of propyphenazone after oral 1963) the given distribution volume is 2 1/kg. administration. Table 1 is a compilation of available The biotransformation of propyphenazone (Figure pharmacokinetic data and it is clearly incomplete. 3) has been investigated only in the rat (Tateishi & Sioufi & Marfil (1978) described a gas chroma- Shimizu, 1976) and in man (Tateishi & Shimizu, tographic method for the determination of propy- 1976; Ehrenthal, Pfleger & Pfleger, 1979). The major phenazone. After oral administration of 220 mg a route of metabolism in both species is demethylation maximum of 1.6 jAg/ml approximately 1.2 h later on the N-2 atom. The enol-glucuronide of N-2- was found. The limit of detection for this method is demethylpropyphenazone is the main metabolite, 125 ng/ml. accounting for about 80% of all the metabolites of 0306-5251/80/140299-10 $01.00 299S 09Macmillan Publishers Ltd 1980 300S M. VOLZ & H.-M. KELLNER C.-H Antipyrinn 50 Arnopn e, --N CH, Aminophanono (Pyvamlkb cH, C -N< DipyroneNovalgin*) CH,-O-SO.Na cX 20 F -<CH, Po mwFn 0 0 Figure 1 C-4-substituted antipyrines ( = 2,3-Dimethyl-l- o 10 I A- t -L-- phenyl-pyrazoline-5-ones). 1 2 3 4 5 6 7 8 Time (h) propyphenazone eliminated in urine. In addition various hydroxylation products occur in smaller Figure 2 Plasma concentrations of propyphenazone in quantities, partly free and partly conjugated. rabbits following an oral dose of 150 mg/kg. Stolz in 1896 substituted the isopropyl radical of t=2.8 +0.6 hours. (Values taken from Naito, 1963.) propyphenazone with a dimethylamino group olds. In elderly people aged 65-86 yr, however, the (Figure 1) to obtain aminopyrine (aminophenazone). plasma concentrations fell approximately five times It was more toxic than antipyrine, but possessed slower than in the 25-30 yr age group (Jori, Di Salle greater antipyretic and analgesic activity. In addition & Quadri, 1972). it had marked anti-inflammatory and spasmolytic An increase in the half-life must also be expected in properties, and was marketed under the name liver disease. In children suffering from hepatitis it Pyramidon® in 1897. was significantly increased to 6.71±3.34 h (Windorfer, There are many reports on the kinetics and Muller & Stehr, 1977). In uraemic patients, in metabolism of amidopyrine in man. contrast, there was no change in plasma concentra- tions and half-life compared with healthy volunteers Aminopyrine (Leber, Harders & Schutterle, 1972). No sex-specific differences were found (Jori et al., 1972). There are Extensive pharmacokinetic studies of aminopyrine indications that aminopyrine elimination kinetics are and its metabolites 4-acetylaminoantipyrine and 4- dose dependent. Phenobarbital may increase the aminoantipyrine have been carried out by Koizumi, elimination rate (Roots, Saalfranck & Hildebrandt, Ueda & Takada (1974). 1975). After oral administration, aminopyrine is absorbed The relative distribution volume is given as 60% of rapidly and almost completely. On average less than the body volume (Roots et al., 1975). According to 2% of the dose appears in the faeces (Brodie & Brodie & Axelrod (1950), aminopyrine is fairly evenly Axelrod, 1950). The maximum plasma concentration distributed throughout body water, similarly to after a single oral dose (Table 2) is usually reached antipyrine. The fraction bound to plasma protein is after 1.5 hours. Between 2.7 and 38 lAg/ml were found, 15%. depending on the dose. In the dose range 150 to After rectal administration absorption is slower and 850 mg the plasma half-lives were 2.1-3.2 hours. The rate and plasma concentrations are lower but more half-lives in saliva were virtually identical to those in constant (Anania, Borroni & Catanese, 1976). the plasma (Vesell, Passananti, Glenwright & A scheme for the metabolism of aminopyrine is Dvorchik, 1975). shown in Figure 4. There were no differences between children and The most important reactions in man are: (1) young adults. Windorfer, Muller & Stehr (1977) demethylation at the 4-position of the pyrazolone found a serum half-life of 2.79+0.53 h in 2 to 1 l-yr- ring with formation of 4-methylaminoantipyrine and Table 1 Pharmacokinetic characteristics of propyphenazone after a single dose in animals and man Author Species Route of Dose Cmax tma administration (mg/kg) (mg) (m.g/ml) (h) (h) Dell et al. (1971) Dog Oral (blood) 16 i.v. (blood) 24 ? 1.0-1.5 0.63 Naito (1963) Rabbit Oral (plasma) 150 42 2 2.8+0.6* Dell et al. (1971) Man Oral (blood) 240 I.3 Sioufi & Marfil (1978) Oral (plasma) 220 1.6 1.2 Ciba Geigy AG Oral (plasma) 220 1.5-3.5 (Basel) Oral (plasma) 440 3.5-12.51 0.5-0.6 1.0-1.5 * Derived from graph. KINETICS & METABOLISM OF PYRAZOLONES 301S r I OHI COOH OH CH, Oxidation AN,N N H O NCH3 Hydroxylation 1'~ IL , Conjugation NN 1 Demethylation H 1%. 0 N NHI .HO N'-N O-, N 'CH 0 C OH Propyphenazone (PPA) Tautomeric forms of N(2)-Demethyl-PPA ir HvdroxvlI 1%IA^ Y.%*Mlation* Hydroxylation H;o HoO NONCH 0 NO N N Ho NN OH IOH OH Conjugation flConjugation| Glucuronides and/or sulphates Figure 3 Metabolism of propyphenazone (PPA) in man. Dotted brackets, hypothetical intermediate; x; glucuronic and/or sulphuric acid. (Based on Tateishi & Shimizu (1976) and Ehrenthal et al. (1979). Table 2 Pharmacokinetic characteristics of aminopyrine after a single oral dose in man Author Dose Cmax tma t+ (mg/kg) (mg) (4g/ml) (h) (h) Vesell et al. (1975) 9 (_450) 6-12* 1.5 2.70±0.29 Jori et al. (1972) (12) 600 17.4* 1.5 2.6* Windorfer et al. (1977) 8-10 (400-500) -10.0 1.5 2.90+0.64 11-13 (500-650) 16.0 1.5 2.50+0.30 14-15 (700-750) -26.0 1.5 3.20±+0.55 16-17 (800-850) -38.0 1.5 2.80+0.60 Anania et al. (1976 (6) 300 10 0.5 I Lavene et al. (1976) (5) 250 2.7+±0.43 1.6+0.2 2.3 Roots et al. (1975) (12) 600 2.05 (24) 1200 3.70+ 1.74 * Derived from graph. 302S M. VOLZ & H.-M. KELLNER a tIH3 CH3-N\ CH3 (D Na 3N Dipyrone 0 N N-CH3 AmincDpyrine CH3 j Demethylation at N(4) CH3 CO-N CH3 CH3-HN _T CH3 O,N~ CH3 0 NN- CH3 4 AMAkA \ MAA AA 9)\ HA UO / /L \ \ z r AA UA CH,CO-HN CH3 HCO-HN CH3 CH3CO-HN CH3 CH3CO-HN CH3 0 N C3 0 N-CH3 o NNH o N-CH AAA FAA N(2)-demethyl-AAA AAA 7 65-70% of dipyrone dose CH3 CH3 CH3-NOSNb ° b~MRNN MRA CH3 N CH3 HN'N ° °AN ($) ~RA 7 =60% of aminopyrine dose Figure 4 Comparison of the metabolism of dipyrone and aminopyrine in man, based on published and reported studies.
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