E. Jähnchen

Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status

The mechanism of cephalosporin‐induced hypoprothrombinemia has been investigated in hospitalized patients, with respect to cephalosporin structure, vitamin K metabolism, and vitamin K status. Cephalosporins containing side chains of N‐methylthiotetrazole (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or methyl‐thiadiazole (cefazolin) all caused the transient plasma appearance of vitamin K1 2,3‐epoxide in response to a 10‐mg intravenous dose of vitamin K1, whereas two cephalosporins without a heterocyclic side chain (cefotaxime and cefoxitin) did not. The plasma accumulation of vitamin K1 2,3‐epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprocoumon. Patients eating normally had plasma vitamin K1 concentrations (176 to 1184 pg/mL) that were within the normal range (150 to 1550 pg/mL) and their clotting tests remained consistently normal for all antibiotics tested. Patients on total parenteral nutrition had lower plasma vitamin K1 concentrations (50 to 790 pg/mL) but normal clotting before starting antibiotic therapy. Of 19 parenterally fed patients, all seven treated with latamoxef developed hypoprothrombinemia, PIVKA‐II and a decrease of protein C within four days whereas 12 patients treated with cefotaxime or cefoxitin showed no clotting changes. Latamoxef‐associated hypoprothrombinemia was readily reversible by 1 mg of vitamin K1 given intravenously, but hypoprothrombinemia and sub‐normal plasma vitamin K1 could recur within two to three days. The data suggest that NMTT‐cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lower nutritional‐vitamin K status predisposes to hypoprothrombinemia.

The enantiomers of phenprocoumon: Pharmacodynamic and pharmacokinetic studies

The pharmacodynamics and pharmacokinetics of the optical enantiomers of phenprocoumon were studied in 5 normal subjects and compared to the racemic mixture. Each subject received a single oral dose of 0.6 mg /kg of racemic, S (−), and R (+) phenprocollmon. S (−) phenprocoumon was 1.6 to 2.6 times as potent as R (+) phenprocollmon when the area under the effect/time curve was used to quantify the total anticoagulant effect per dose. Comparing the plasma concentrations that elicited the same anticoagulant effect, S (−) phenprocoumon was 1.5 to 2.5 times as potent as R (+) phenprocoumon. The anticoagulant activity of the racemic mixture was between that of the enantiomers. There was no distinct difference in the rate of elimination between the enantiomers. The apparent volume ()f distribution and the plasma clearance for S (−) phenprocoumon were less than those for R (+) phenprocoumon. When the binding of the enantiomers to human serum albumin was compared, S (−) phenprocoumon was more highly bound than R (+) phenprocoumon. The protein binding of racemic phenprocoumon was between that of the enantiomers. The results show that S (−) phenprocoumon is a more potent anticoagulant than R (+) phenprocoumon and that the pharmacokinetic d~fferences between the enantiomers are due mainly to differences in their distribution.

Lorcainide. II. Plasma concentration-effect relationship.

The effects of lorcainide were studied in 17 patients after single doses (2 mg/kg intravenously; 6 mg/min intravenously over 30 to 40 min; 150, 300, and 500 mg orally) and during long‐term antiarrhythmic treatment (200 to 600 mg daily orally). The frequency of ventricular premature contractions (VPCs), the changes in the electrocardiogram (ECG), and the plasma concentration of lorcainide were determined. The widening of the QRS complex observed after single doses of lorcainide mimicked the time course of plasma concentration permitting the construction of linear relationships between both parameters. After oral administration lower plasma concentrations were required to produce the same QRS widening than after intravenous administration. Patients differed considerably in the slopes of these plasma concentration‐effect curves. After repeated intravenous infusions of lorcainide, plasma concentration‐effect relationships were constructed for both antiarrhythmic and ECG effects. During drug infusion higher concentrations of lorcainide were required to induce antiarrhythmic and toxic effects (QRS widening and PQ prolongation) than during the postinfusion period. Whereas during the infusion period the plasma concentration‐effect curves for both effects followed the same slope, during the postinfusion period VPCs were remarkably more sensitive to plasma concentration than the changes in the ECG. Suppression of VPCs during long‐term treatment with lorcainide was accompanied by small changes in the ECG which were related to the dose and plasma concentration of lorcainide. Thus, the lorcainide regimen may be monitored by careful inspection of the ECG.

Lorcainide. I. Saturable presystemic elimination.

The disposition of lorcainide after single oral and intravenous doses and during long‐term oral and intravenous dosing was investigated in 17 patients with chronic ventricular premature contractions. Lorcainide is thought to be eliminated mainly by metabolism in the liver. After a single intravenous (IV) dose of 2 mg/kg, the mean systemic clearance was 1.67 1/min, which is equal to the normal liver blood flow rate. When 10 of these patients were treated with 2 different single oral doses, the fraction of the dose reaching the systemic circulation (F) rose from a mean of 0.27 to 0.50 when the dose was increased from 150 to 300 mg. After long‐term oral dosing F increased further and approached unity in some patients. The plasma concentration of the N‐dealkylated metabolite rose and exceeded that of the parent drug when long‐term IV treatment was replaced by long‐term oral treatment. Simultaneous measurements of plasma concentration of lorcainide in the abdominal aorta and hepatic vein in 2 patients showed a high hepatic lorcainide uptake after a single IV dose. When 1 of these 2 patients was treated orally for 3 days (3 × 100 mg/day) concentration differences in afferent and efferent liver blood disappeared. Lung did not extract measurable amounts of lorcainide in 2 patients, in whom the plasma lorcainide concentrations were measured in the pulmonary artery and thoracic aorta over a period of 30 min after a single IV dose of 2 mg/kg. Our results suggest that lorcainide is subject to saturable presystemic elimination, most likely due to a saturation of hepatic extraction.

Age-dependent differences in the anticoagulant effect of phenprocoumon in patients after heart valve surgery

AbstractObjective: An enhanced response to warfarin and an increased risk of major bleeding has been observed in older patients. The reason for this increase in sensitivity remains unknown. It could be due to pharmacodynamic reasons, pharmacokinetic reasons, or both. Methods: We therefore followed an anticoagulant regimen with phenprocoumon in 19 older (76 years) and 19 younger patients (50 years) following heart valve replacement. INR values were determined frequently. At the 4th and around the 24th day after starting treatment with phenprocoumon, we also measured the total and unbound plasma concentration of phenprocoumon. Results: The dose requirement to obtain the desired anticoagulant effect was significantly lower in the older patients than in the younger patients (26.3 vs. 37.3 μg · kg−1 · day−1). The total plasma concentration (2.19 vs. 2.43 μg · ml−1), the percentage unbound drug in the plasma (0.61 vs. 0.64%) and the unbound plasma concentration (13.8 vs. 15.1 ng · ml−1) did not differ significantly between older and younger patients. The dose-adjusted INR (INR/dose) was higher in the older patients (110 vs. 67) but the INR adjusted for the unbound plasma concentration (INR/Cuss) which reflects the intrinsic sensitivity to the drug, was not significantly different (192 vs. 173). However, the older patients had an about 30% significantly lower metabolic clearance based on unbound drug (84 vs. 115 ml · kg−1 · h−1). Conclusions: Older patients (> 70 years) require a dose approximately 30% lower than younger patients (< 160␣years). Pharmacokinetic reasons (reduced metabolic clearance) are mainly responsible for the lower dose requirement of the older patients after heart valve surgery.

Stereoselective drug distribution and anticoagulant potency of the enantiomers of phenprocoumon in rats

The elimination, distribution and anticoagulant activity of S(—)‐, R(+)‐, and R,S(±)‐phenprocoumon were determined in male Wistar‐Lewis rats after intravenous injection of a single dose of 0·6 mg kg−1. From the plasma concentrations which elicited the same anticoagulant effect, S(—)‐phenprocoumon was 4 to 5 times more potent than R(+)‐phenprocoumon. The potency of the racemate was between those of the enantiomers. The mean biologic half‐life of the S(—)‐enantiomer was shorter (12·5 h) than that of R(+)‐phenprocoumon (17·8 h). No differences were observed in the apparent volume of distribution. However, the mean liver: plasma concentration ratio was higher for the S(—)‐(6·9) than for the R(+)‐enantiomer (5·2). At a total concentration of 16·8 μg ml−1 the percentage of unbound drug in rat serum was significantly higher for the S(—)‐ (1·13%) than that for the R(+)‐enantiomer (0·76%). Values obtained for the racemate were always between those of the enantiomers. It is concluded that stereoselective differences in the distribution between plasma and liver, and consequently in the rate of elimination are most likely due to stereoselective differences in serum protein binding. The greater anticoagulant potency of the S(—)‐ over the R(+)‐enantiomer, cannot be explained primarily by the observed pharmacokinetic differences.

Interruption of the enterohepatic circulation of phenprocoumon by cholestyramine.

The effect of cholestyramine (12 gm/day divided into 3 doses) on the pharmacokinetics and pharmacodynamics of a single intravenous dose (30 mg) of phenprocoumon was studied in 6 normal subjects. Cholestyramine treatment led to an increase in the rate of elimination of phenprocoumon in all. Total clearance increased 1.5‐ to 2‐fold. The total anticoagulant effect per dose was considerably reduced during treatment with cholestyramine. Binding studies in vitro showed that phenprocoumon is strongly bound to cholestyramine and that at a given cholestyramine concentration the percentage of phenprocoumon bound remained constant over a large concentration range of phenprocoumon. The results suggest that phenprocoumon undergoes extensive enterohepatic recycling in man which can be effectively interrupted by cholestyramine.

Relationship between pharmacokinetics and hemodynamic tolerance to isosorbide-5-mononitrate

SummaryHealthy male volunteers received three different dose regimens of a controlled-release form of isosorbide-5-mononitrate (IS-5-MN; 60 mg per tablet). Dose regimen I consisted of a single daily dose of 60 mg given for 5 days. Dose regimen 11 was started with a dose of 60 mg, followed by 30 mg 12 h later and thereafter every 8 h. The last dose, on the 5th day was again 60 mg. In dose regimen III60 mg followed by 30 mg 6 h later were administered every day for 5 days. The peripheral arterial and venous effects of IS-5-MN during the first and last dosing interval were followed by changes in the finger pulse curve, standing systolic blood pressure, heart rate, and venous distensibility. Plasma concentrations of IS-5-MN were measured frequently following the first and the last dose. Following dose regimen I all hemodynamic effects produced by the first dose were maintained during the study. The maximal plasma concentrations were about 400 ng/ml and the trough value, lower than 100 ng/ml. Following dose regimen II the hemodynamic effects of IS-5-MN and sublingual glyceroltrinitrate were completely abolished on the 5th day. Trough plasma concentrations were approximately 300 ng/ml during the entire study period. Following dose regimen III pronounced hemodynamic effects were seen on the 1st day. However, a significant attenuation of the hemodynamic effects was measured on the 5th day, when trough plasma concentrations were between 100 and 230 ng/ml. There was a significant negative correlation between the magnitude of hemodynamic effect remaining on the 5th day (measured by the area under the finger pulse curve) and the trough plasma concentration. Thus, the maintenance of minimum plasma concentrations of IS-5MN of 300 ng/ml or higher produces a rapid development of hemodynamic nitrate tolerance, whereas no tolerance was found when the plasma concentrations were allowed to decline below 100 ng/ml before the next dose was given. A significant attenuation of hemodynamic effects was found when minimum plasma concentrations were between 100 and 230 ng/ml. The degree of attenuation in this concentration range increased with increasing trough plasma concentrations.

Die Bedeutung der Benzolringe bei der Eiweißbindung von Promazin und Chlorpromazin

SummaryThe different binding ability of bovine serum albumin for promazine and chlorpromazine suggested that the benzene rings of the phenothiazine nucleus are involved in the protein binding. Simple aromatic substances such as benzoic acid, salicylic acid, acetylsalicyclic acid and nicotinic acid were able to displace the phenothiazine derivates from their binding to bovine serum albumin. On the other hand alicyclic compounds such as cyclohexylamine and tranexamic acid had no displacing activity. From these results it was concluded that hydrophobic interactions between the phenothiazine derivatives and the protein are mediated by the benzene rings within the phenothiazine molecules.ZusammenfassungDie unterschiedliche Bindungsfähigkeit von Promazin und Chlorpromazin in 1% iger und 4% iger Rinderserumalbuminlösung ließ eine Beteiligung der Phenothiazinbenzolringe an der Eiweißbindung vermuten. Durch einfache aromatische Substanzen wie Benzoesäure, Anilin, 2,6-Dihydroxybenzoesäure, Salicylsäure, Acetylsalicylsäure und Nicotinsäure konnten die Phenothiazinderivate aus ihrer Bindung an Rinderserumalbumin verdrängt werden. Dagegen zeigten alicyclische Verbindungen wie Cyclohexylamin und Tranexamsäure keinen Verdrängungseffekt. Aus diesen Befunden wurde auf eine hydrophobe Wechselwirkung zwischen den Benzolringen der Phenothiazinderivate einerseits und des Albumins andererseits geschlossen.

Disposition of azapropazone in chronic renal and hepatic failure.

SummaryThe disposition of azapropazone 600 mg i.v. was investigated in 6 healthy subjects, 13 patients with cirrhosis and 8 patients with renal failure. In healthy subjects the elimination half-life was 12.2±2.1 h (mean ± SD), the volume of distribution 10.6±3.31 and the total clearance was 597±135 ml·h−1. Renal clearance accounted for about 62% of the total clearance. The free fraction of azapropazone in the plasma was 0.0045±0.0006. The patients with cirrhosis were divided into Group I with modest and Group II with severe impairment of liver function. In Group I the total clearance of azapropazone was not significantly different from that in healthy subjects. There was a 2.5-fold increase in its free fraction in plasma, and a reduction in the free drug clearance to about half that in healthy subjects. In Group II patients total clearance was reduced to about 20% of normal. This was partly due to reduced non-renal clearance but mainly to impaired renal clearance of azapropazone. The diminished renal clearance was considered at least in part to represent a drug-induced impairment of renal function, as there was a concomitant reduction in creatinine clearance. The free fraction of azapropazone in the plasma was markedly enhanced (>0.02), and simultaneously, free drug clearance was drastically reduced, to about 2% of that in healthy subjects. In patients with renal failure the total clearance was diminished, depending on the degree of impairment of kidney function. Anephric patients were estimated to have about one third of the total clearance in normal subjects. The free fraction of azapropazone in the plasma was increased in 4 of the 8 patients. It is concluded that patients with cirrhosis and modest impairment of liver function may require about half the normal dose of azapropazone, since free drug clearance is reduced by about 50%. Patients with severe impairment of liver function are expected to be highly susceptible to dose-related side effects, since the pronounced increase in the free fraction in plasma and the decreases in renal and non-renal clearance lead to marked reduction in free drug clearance and so to accumulation of free drug in the body. In patients with renal failure the dose of azapropazone should be reduced according to the degree of impairment of kidney function and plasma protein binding of the drug.