Ch. Staiger

Induction of drug metabolizing enzymes by sulfinpyrazone

SummaryA previous interaction study of sulfinpyrazone (Anturano®) suggested that it induced microsomal drug metabolizing enzymes in the liver. To verify this finding the effect of sulfinpyrazone 800 mg per day for four weeks was investigated in ten healthy volunteers. Both the therapeutic actions of sulfinpyrazone, the uricosuric and the antiaggregating effects, were demonstrated (p<0.05). The influence on the microsomal drug metabolizing system in the liver was demonstrated by an increase in serum-λ-glutamyl transpeptidase from 15.1 to 23.3 U/l (p>0.05), a significant increase in the urinary excretion of d-glucaric acid (29.6 to 77.9 µMol/24 h,p<0.05) and an increase in antipyrine clearance from 50.3 ml/min to 83.9 ml/min (p<0.05). The possibility of enhancement of drug metabolism during treatment with sulfinpyrazone in combination with other drugs should be kept in mind.

Lack of effect of cimetidine on action of phenprocoumon.

SummaryIn patients on oral warfarin, nicoumalone and phenindione an increase in the anticoagulant effect has been described during concomitant treatment with cimetidine. Therefore the effect of cimetidine on the steady state dynamics of phenprocoumon has been investigated in ten outpatients. No change in the anticoagulant effect of phenprocoumon was observed during or after two weeks on cimetidine, as measured by the thrombotest coagulation method, prothrombin time, fibrinopeptide A concentration and plasma phenprocoumon level. The data show that cimetidine does not interact with the metabolism of phenprocoumon in contrast to warfarin. Thus, phenprocoumon maintenance therapy when combined with concomitant cimetidine treatment can be considered not to carry an increased risk of haemorrhagic complications.

Effect of single and multiple doses of sulphinpyrazone on antipyrine metabolism and urinary excretion of 6-beta-hydroxycortisol

SummarySulphinpyrazone decreases the plasma clearance of tolbutamide and S-warfarin and increases the clearance of R-warfarin, theophylline and antipyrine. In order to determine whether sulphinpyrazone is an inducer or inhibitor or both of oxidative drug metabolism, antipyrine and its metabolites as well as 6-beta-hydroxycortisol were measured in urine before, 24 h and after 23 days of chronic administration of sulphinpyrazone (4×200 mg/day). During chronic treatment sulphinpyrazone increased the ratio of 6-beta-hydroxycortisol to the 17-hydroxycorticosteroids by 70% (p<0.02). The renal clearance of the main oxidative metabolites of antipyrine (4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine) were increased after sulphinpyrazone (p<0.02). Except for norantipyrine, no change in total excretion of antipyrine and its metabolites occurred after 24 h or after 23 days. It is concluded that sulphinpyrazone induces the enzymes which metabolize antipyrine and cortisol.

Pharmacokinetics of sulphinpyrazone and its major metabolites after a single dose and during chronic treatment

SummaryThe pharmacokinetics of sulphinpyrazone and its major metabolites (sulfide, sulfone, p-hydroxysulfone and p-hydroxy-sulphinpyrazone) were investigated in 9 volunteers after a single oral dose as well as after chronic treatment for 23 days. Chronic administration of sulphinpyrazone, in comparison with a single oral dose, led to significant changes in plasma AUC (115.86 to 42.90 mg/l·h), in renal clearance (1.06 to 1.80l/h), in hepatic intrinsic clearance (319.0 to 598.0l/h), and in the unbound fraction in plasma 1.15 to 1.69%) and in tissue (2.73 to 1.31%). The volume of distribution changed from 20.24 to 52.041. The steady state concentrations predicted from the single dose were significantly higher than the values found after chronic treatment. The results suggest that sulphinpyrazone induces its own metabolism. The metabolism of the sulfone, p-hydroxysulfone and the p-hydroxy-sulphinpyrazone to further degradation products was also induced. Chronic treatment with sulphinpyrazone reduced the plasma AUC of the sulfide and caused a decrease in its elimination half-life (20.9 to 14.3 h). Since considerable amounts of the sulfide are formed in the G.I. tract, it is suggested that besides the induction of metabolism, bacteria which reduce sulphinpyrazone to the sulfide may also be responsible for the observed pharmacokinetic changes.

The effects of a combination of cigarette smoking and oral contraception on coagulation and fibrinolysis in human females

SummaryOral contraception as well as cigarette smoking influence haemostasis. The simulataneous effect of both on blood coagulation and fibrinolysis was studied in nine female smokers. While continuing oral contraception after a 4-week abstinence from smoking the concentration of fibrinogen, antithrombin III and alpha1-Antitrypsin decreased (P<0.01 orP<0.04) and of plasminogen increased (P<0.03). The other coagulation parameters remained unchanged. Although all determinations of these parameters were in the normal range, the observed trends were statistically significant. The concentrations of the fibrinopeptide A and B 15–42 did not differ. It is concluded that the observed alteration is caused by cessation from cigarette smoking.

A Rapid and Sensitive Method for the Determination of Phenazone (Antipyrine®) using Gas-Liquid-Chromatography with Nitrogen Detection

A simple and rapid method for the quantitative determination of antipyrine, using gas-liquid-chromatography with nitrogen detection, is described. Only one extraction step is needed, the recovery is 91.2% and the precision varies between 3.14--1.96%. The lower limit of quantitative assay reached 0.1 mg/l plasma. During routine handling the method was easy, quick and cheap.

Enhanced drug metabolism after sulfinpyrazone treatment in patients aged 50 to 60 years

SummaryThe induction of liver drug metabolism was investigated in five patients before and after the administration of 800 mg sulfinpyrazone daily for 4 weeks, by using antipyrine plasma-pharmacokinetics and by determining urinary excretion of 6-β-OH-cortisol and serum gamma-glutamyl-transpeptidase (GGT) activity. Antipyrine half-life was shortened in all patients from a mean value of 12.3±3.9 h to 7.8±2.0 h and antipyrine clearance was increased from 39.0±16.0 ml/min to 57.6±13.7 ml/min. In contrast the volume of distribution of antipyrine was unaffected; the values being 38.0±8.6 liters and 37.4±5.7 liters, respectively. In all patients the excretion of 6-β-OH-cortisol in the urine went up from 65.0±25.7 µg/24 h to 346.8±193.4 µg/24 h. The ratio 6-β-OH-cortisol/free cortisol changed from 4.1 to 15.8. After 21 days of treatment the GGT increased from 17.4±4.9 units/liter to 32.6±12.5 units/liter The data presented confirm that sulfinpyrazone induces drug metabolism in patients of the older age group. Interactions between sulfinpyrazone and other drugs given simultaneously must be borne in mind.ZusammenfassungSulfinpyrazon (Anturano) wird als Uricosuricum wie als Thrombozytenaggregationshemmer meist gleichzeitig mit anderen Medikamenten verabreicht. Die Kenntnis möglicher Einflüsse auf den Arzneimittelstoffwechsel ist für eine sichere medikamentöse Therapie unerläßlich. Deshalb wurde bei fünf Patienten mit einer Indikation für die Sulfinpyrazon-Therapie der Einfluß einer täglichen Gabe von 800 mg Sulfinpyrazon über 4 Wochen auf den hepatischen Arzneimittelstoffwechsel überprüft.Als Parameter für eine Steigerung des Arzneimittelmetabolismus war die Antipyrin-Plasma-Halbwertszeit bei allen Patienten verkürzt, im Mittel von 12,3±3,9 auf 7,8±2,0 h und die Antipyrin-Clearance von 39,0±16,0 auf 57,6±13,7 ml/min gesteigert. Erwartungsgemäß konstant blieb das Verteilungsvolumen mit 38,0±8,6 bzw. 37,4±5,71. Die Urin-Ausscheidung von 6-β-OH-Cortisol stieg von 65,0±025,7 auf 346,8±193,4 µg/24 h an und das Verhältnis 6-β-OH-Cortisol/freies Cortisol von 4,1 auf 15,8. Nach dreiwöchiger Behandlung war die GGT von 174,±4,9 auf 32,6±12,5 U/l erhöht.Die Ergebnisse zeigen, daß eine Behandlung mit Sulfinpyrazon auch bei 50–60jährigen Patienten zu einer Induktion des Arzneimittelstoffwechsels führt. Vor allem bei gleichzeitiger Gabe mit oralen Antikoagulantien sollte dies neben der initialen Verstärkung des Antikoagulantieneffektes berücksichtigt werden.