E. Walter

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.

Does chronic aspirin treatment increase blood pressure in man

SummaryIn postmyocardial infarction patients longterm aspirin treatment with 1.5 g/day led to a significant increase in systolic and diastolic blood pressure after 6 months. This could not be found in the placebo- and the phenprocoumon-treated patients. After one year the blood pressure behaviour was the same in all three treatment groups. As nonsteroidal antirheumatic drugs can produce hypertension in animals, probably due to inhibition of prostaglandin synthesis, blood pressure control in longterm aspirin treatment is advisable.ZusammenfassungNach 6 Monaten Therapie mit 1,5 g Acetylsalizylsäure täglich wurde bei Postinfarkt-Patienten ein signifikanter Anstieg des systolischen und diastolischen Blutdrucks beobachtet. Ein solches Ansteigen des Blutdrucks konnte bei den mit Placebo oder Phenprocoumon Behandelten nicht nachgewiesen werden. Ein Jahr nach Therapiebeginn war das Blutdruckverhalten gleich in allen drei Therapiegruppen. Da auch bei Tieren mit nichtsteroidalen Antirheumatika ein Hochdruck erzeugt werden konnte, wahrscheinlich durch Hemmung der Prostaglandinsynthese, ist die regelmäßige Blutdruckkontrolle während einer Langzeit-Aspirin-Therapie ratsam.

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.

Determination of the anticoagulant phenprocoumon in human plasma and urine by high-performance liquid chromatography

The determination of the anticoagulant phenprocoumon in plasma, after acidification and extraction with 1,2-dichloroethane was effected through isocratic high-performance liquid chromatography; a C18 reversed-phase column was used as stationary phase using aqueous acetonitrile as eluent and UV detection at 313 nm; p-chlorophenprocoumon was used as internal standard. A high proportion of phenprocoumon in urine is eliminated as the glucuronide and must be hydrolyzed enzymatically before extraction; the same column and detector as for plasma were used, but with gradient elution. The method was used in the range 0.1-5 mg/1, the sensitivity was 0.1 mg/1 for plasma and 0.02 mg/1 for urine, the precision was in the range 3-5% and the absence of interference due to other anticoagulants, drugs or endogenous compounds allows the specific determination of phenprocoumon in plasma and urine from patients and volunteers in clinical relevant cases, drug interaction, compliance, toxicological and pharmacokinetic studies.

[The intraindividual variation of fibrinolytic activity in volunteers (author's transl)].

In five volunteers fibrinolytic activity has been measured five times over a period of six weeks during increasing values of circadian rhythm. Euglobulinlysis-time, paper fibrinolysis, fibrinogen, plasminogen, alpha1-antitrypsin, alpha2-makroglobulin, thrombino-coagulase-time and fibrin-split-products were used in one study. An increase of fibrinolytic activity in the mooning was observed in all volunteers. Intraindividual variation of values is considerable but less than variation of values compared interindividually. Moreover variation was smaller at noon than in the time before noon. In clinical trial of the short-time effect of drugs the period of the plateau of the fibrinolytic activity should be used because of its smaller variation of values. Furthermore, in this period the intraindividual variation of the fibrinolytic activity is smaller than during increasing slope of the circadian rhythm of fibrinolysis. Intraindividual control should be granted.SummaryIn five volunteers fibrinolytic activity has been measured five times over a period of six weeks during increasing values of circadian rhythm. Euglobulinlysis-time, paper fibrinolysis, fibrinogen, plasminogen, α1-antitrypsin, α2-makroglobulin, thrombinocoagulase-time and fibrin-split-products were used in one study. An increase of fibrinolytic activity in the mooning was observed in all volunteers. Intraindividual variation of values is considerable but less than variation of values compared interindividually. Moreover variation was smaller at noon than in the time before noon.In clinical trial of the short-time effect of drugs the period of the plateau of the fibrinolytic activity should be used because of its smaller variation of values. Furthermore, in this period the intraindividual variation of the fibrinolytic activity is smaller than during increasing slope of the circadian rhythm of fibrinolysis. Intraindividual control should be granted.ZusammenfassungBei 5 Probanden wurde über einen Zeitraum von 6 Wochen fünfmal die Anstiegsphase im Tagesrhythmus der fibrinolytischen Aktivität untersucht. Als Parameter wurden die Euglobulinlyse-Zeit und die Papierfibrinolyse, die Plasmaproteine, Fibrinogen, Plasminogen, α1-Antitrypsin und α2-Makroglobulin sowie die Thrombinocoagulase-Zeit und die Fibrinspaltprodukte erfaßt. Es zeigte sich bei allen Probanden der Anstieg der Fibrinolyse am Vormittag. Die Schwankungsbreite der fibrinolytischen Aktivität ist intraindividuell kleiner als bei einem interindividuellen Vergleich. Weiterhin zeigt sie mittags eine geringere Streuung als vormittags.Bei Untersuchungen zur klinischen Prüfung eines Soforteffektes von Arzneimitteln auf die Fibrinolyse sollte der Zeitraum der Plateauphase der fibrinolytischen Aktivität gewählt werden, um die Streuung der Ausgangswerte möglichst gering zu halten. Weiterhin ist die intraindividuelle Streuung der fibrinolytischen Aktivität in diesem Zeitraum geringer als während der Anstiegsphase im Rahmen des circadianen Rhythmus der Fibrinolyse. Eine intraindividuelle Kontrolle muß gewährleistet werden.

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.