Bernd Rosenkranz

Effect of single doses of cimetidine and ranitidine on the steady‐state plasma levels of midazolam

H2‐Receptor antagonists may interfere with the pharmacokinetics of concomitantly administered drugs. Our study was designed to investigate whether cimetidine or ranitidine influence the disposition and sedative effect of midazolam. The effect of single oral doses of 800 mg cimetidine, 300 mg ranitidine, or placebo on the steady‐state concentrations of midazolam was examined in a randomized crossover study in eight healthy subjects. A midazolam steady‐state concentration was achieved by an intravenous bolus (0.05 mg/kg)‐infusion (0.025 mg/kg/hr) technique. Plasma concentrations of midazolam, cimetidine, and ranitidine and the pharmacodynamic response to midazolam (choice reaction time, sedation index) were monitored throughout the 10‐hour infusion. Cimetidine significantly increased the mean (± SD) steady‐state plasma concentration of midazolam from 56.7 ± 7.8 to 71.3 ± 19.6 ng/ml (P = 0.004). In contrast, the steady‐state midazolam concentration after ranitidine dosing (61.8 ± 6.8 ng/ml) did not differ significantly from that after placebo. No change in choice reaction time or sedation index was detected after cimetidine or ranitidine dosing. Nevertheless, in contrast to ranitidine, the recently advocated once‐daily dosing of cimetidine has a potential for hepatic drug interaction that should be considered before its coadministration with drugs that have a narrow therapeutic index.

Famotidine, a new H2-receptor antagonist, does not affect hepatic elimination of diazepam or tubular secretion of procainamide

SummaryIn 8 healthy male volunteers the pharmacodynamic responses to a single dose of diazepam and a single dose of procainamide were assessed before and after pre-treatment with the H2-receptor antagonist famotidine in a randomized crossover study. The pharmacokinetics of diazepam and procainamide were also studied, and the binding of famotidine to human liver microsomes was also measured. Cimetidine induced binding changes with a spectral dissociation constant (Ks) of 0.87 mM, whereas famotidine produced no measurable spectral alteration in concentrations up to 4 mM. The elimination half-life (t1/2: 45.6 h) and total plasma clearance (CL: 0.28 ml/min/kg) of diazepam were not significantly altered by famotidine (t1/2=39.0±11.4 h; CL =0.31±0.08 ml/min/kg). Similarly, there was no enhancement of the sedative effect of diazepam by famotidine. The pharmacodynamics and pharmacokinetics of procainamide and N-acetylprocainamide (NAPA), too, were not significantly changed by famotidine: procainamide t1/2 2.9 vs 3.0 h under famotidine and renal clearance (CLR) 436 vs 443 ml/min; and NAPA CLR 195 vs 212 ml/min under famotidine. The data suggest that famotidine, in contrast to cimetidine, does not affect the pharmacokinetics of diazepam (hepatic elimination) or procainamide (tubular secretion). This new H2-receptor antagonist appears to be devoid of an interaction potential for either type of drug elimination.

Identification of the major metabolite of prostacyclin and 6-ketoprostaglandin F1α in man

Abstract Human volunteers were infused with 3 H- and 2 H-labeled prostacyclin or 3 H-labeled 6-ketoprostaglandin F 1α and, in separate experiments, with the unlabeled prostanoids. The urine was purified by different chromatographic steps and finally separated into several fractions by high-performance liquid chromatography. The major fractions contained 20.5 and 23.0% of the eluted radioactivity for the metabolites of prostacyclin and 6-ketoprostaglandin F 1α , respectively. The structure of both metabolites was identified by gas-liquid chromatography-mass spectrometry as dinor-6-ketoprostaglandin F 1α . It is concluded that the major metabolite of prostacyclin and 6-ketoprostaglandin F 1α in man is dinor-6-ketoprostaglandin F 1α .

Prostacyclin metabolites in human plasma

The major metabolites of prostacyclin (PG12) in human plasma have been determined after intravenous infusion of tritium‐labeled and unlabeled prostacyclin. Plasma was extracted and chromatographed. On high‐pressure liquid chromatography (HPLC), several radioactive peaks could be resolved. The major peak containing 41.6% of the radioactivity had the retention volume of authentic 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α), the stable in vitro hydrolysis product of prostacyclin. When the material of this peak was derivatized to the methoxime methyl ester trimethylsilyl ether and analyzed by gas chromatography–mass spectrometry, the fragments m/z 508 and 598, which are characteristic of this derivative of 6‐keto‐PGF1α were detected. A much smaller peak representing 6.6% of the radioactivity eluted from HPLC with the same retention volume as dinor‐6,15‐diketo‐13,14‐dihydro‐PGF1α. On gas chromatography–mass spectrometry this material resulted in the fragments m/z 527, 468, 437, and 347, which are characteristic for this prostanoid. Finally, 10.1% of the radioactivity with ions m/z 571, 481, 391, and 354 on mass spectrometric analysis could be identified as dinor‐6,15‐diketo‐13,14‐dihydro‐20‐carboxyl‐PGF1α. it is concluded that 6‐keto‐PGF1α represents the major breakdown product of prostacyclin in human plasma, in addition, dinor‐6,15‐diketo‐13,14‐dihydro‐PGF1α and its ω‐oxidized analog could be identified circulating metabolites.

Metabolic disposition of prostaglandin E1 in man

Metabolism of [17, 18-3H]prostaglandin E1 was investigated in three healthy male volunteers during intravenous infusion. The infusion rate was 5.0 ng/kg per min. Blood samples were obtained before the end of the infusion as well as 5, 10, 20, 40, 90 and 180 min afterwards; urine and feces were collected until 96 and 72 h, respectively, after the experiment. All samples were analyzed for radioactivity. Urine was further chromatographed, including by high-pressure liquid chromatography, and subsequently analyzed by gas chromatography-mass spectrometry. Radioactivity in plasma rapidly declined during the first 10 min after termination of the infusion, and then was eliminated exponentially with a mean half-life of 181 min, probably reflecting slow excretion of one or more metabolite. 12% of the administered radioactivity could be recovered from feces and 88% from urine. From the radioactive material obtained from urine the following metabolites could be identified (each number represents data of one volunteer): 7 alpha-hydroxy-5,11-diketotetranor-prostane-1,16-dioic acid (10.4, 20.4 and 30.1%), 7 alpha-hydroxy-5,11-diketotetranor-prostanoic acid (8.2, 6.9 and 9.3%), 5 alpha, 7 alpha-dihydroxy-11-ketotetranor-prostane-1,16-dioic acid and its delta-lactone (together accounting for 4.1, 2.1 and 3.8%).

Glucocorticoid effect on arachidonic acid metabolism in vivo.

Glucocorticoids have been shown in in vitro systems to inhibit the release of arachidonic acid metabolites, namely prostaglandins (PGs) and leukotrienes, apparently, via the induction of a phospholipase A2 inhibitory protein, called lipocortin. On the basis of these in vitro results, it has been suggested that inhibition of eicosanoid production is, at least partially, responsible for the well-known anti-inflammatory effect of glucocorticoids. There is, however, no firm evidence proving that glucocorticoids also inhibit prostaglandin or leukotriene synthesis in vivo. In a series of studies, we have investigated the effects of anti-inflammatory steroids on the production of six different cyclo-oxygenase products in vivo. Urinary prostaglandin (PG) E2(1), PGF2 alpha, thromboxane B2 (TxB2), 6-keto-PGF1 alpha, and the major urinary metabolites of the E and F PGs, PGE-M and PGF-M, respectively, were determined by radioimmunoassay and by GC-MS. Administration of pharmacological doses of dexamethasone to rabbits failed to inhibit urinary excretion rates of PGE2, TxB2, 6-keto-PGF1 alpha and that of PGE-M and PGF-M. In contrast, urinary PGF2 alpha was slightly reduced by dexamethasone. In further experiments the effect of dexamethasone was studied in humans. Urinary excretion rates of PGE2, PGE-M, PGF-M, 2,3-dinor TxB2 and 2,3-dinor 6-keto-PGF1 alpha were not suppressed by dexamethasone. Collagen-induced platelet TxB2 formation and platelet aggregation was also unaltered. To test one possible explanation for the apparent discrepancy between in vitro and in vivo effects of glucocorticoids on arachidonic acid metabolites we investigated the effects of dexamethasone in vivo on basal and on antidiuretic hormone-stimulated renal PG synthesis. Dexamethasone treatment failed to inhibit both basal and antidiuretic hormone-stimulated PGE2 and PGF2 alpha production. We conclude that glucocorticoids in vivo do not decrease the basal rate of total body, kidney and platelet prostanoid synthesis, and that dexamethasone does not inhibit renal PG production when it is elevated by antidiuretic hormone, a physiological stimulus. Thus, a differential effect of glucocorticoids on basal vs stimulated PG synthesis cannot account for the discrepancy between in vivo and in vitro effects.

Falsely elevated digoxin concentrations in patients with liver disease

Immunoreactive digoxin was determined in blood samples of 73 patients with liver disease who did not take any cardiac glycoside. Seventeen of these patients reproducibly showed false-positive results, as much as 3.6 ng/ml. Patients with concomitant renal disease had higher assay results (mean 1.9 n/ml) than patients with normal renal function (mean 0.6 ng/ml). It is concluded that blood of a number of patients with liver disease of different causes contains a substance that interferes with digoxin radioimmunoassay.

Investigations on Renal Prostaglandins by Gas Chromatography—Mass Spectrometry

The large number of arachidonic acid metabolites present in the mammalian kidney and urine require highly sensitive and specific analytical methods for the determination of very small amounts of chemically closely related prostanoids. Gas chromatography—mass spectrometry (GCMS) combines a high degree of specificity and sensitivity, especially if preceded by high-performance liquid chromatographic (HPLC) purification and preseparation of biological samples. A further improvement of sensitivity is added by using glass capillary columns instead of the “classical,” standard packed columns. Elucidation of the role of arachidonic acid metabolites in renal physiology and pathophysiology necessitates both a highly sophisticated analytical method as well as special marker prostaglandins (PGs) to serve as indicators for the different renal functions.

Urinary and Systemic Metabolites of Prostacyclin in the Perfused Rabbit Kidney

Rabbit kidneys were isolated and perfused with a solution to which tritiated or unlabeled prostacyclin was added continuously. The ureteral and venous effluents were collected separately and chromatographed. The peaks obtained by high-pressure liquid chromatography were analyzed using gas chromatography-mass spectrometry. The characteristic fragments of dinor-6-keto-PGF1 alpha could be detected from ureteral and venous effluents and represented material corresponding to 9.6 and 9.1% of the radioactivity recovered from chromatography, respectively. In addition, 39.2% (ureteral effluent) and 58.2% (renal venous effluent) of the radioactivity could be identified as 6-keto-PGF1 alpha, the stable in vitro hydrolysis product of prostacyclin. These results show that the kidney is able to degrade prostacyclin by beta-oxidation and that dinor-6-keto-PGF1 alpha formed in the kidney can be detected in both the vascular and urinary compartments.

Effects of Sulfinpyrazone on Renal Function and Prostaglandin Formation in Man

Sulfinpyrazone (800 mg/day for 6 days) significantly reduced the excretion of the main urinary prostaglandin E metabolite by 54% in 6 healthy female volunteers. While sulfinpyrazone did not affect inulin clearance, clearances of creatinine and PAH were significantly diminished by 18.0 and 44.7%, respectively. In the anaesthetized dog sulfinpyrazone decreased PAH clearance and PAH extraction concomitantly without affecting renal blood flow. These results show that clearances of creatinine and PAH do not reliably reflect glomerular filtration and renal perfusion, respectively, during sulfinpyrazone administration. Whereas sodium balance and body weight were not significantly different between the first control period and sulfinpyrazone administration, net sodium excretion significantly increased from 121.6 +/- 5.4 mEq/day during sulfinpyrazone treatment to 139.3 +/- 6.6 mEq/day during the following control period, while body weight significantly decreased indicating modest sodium retention during drug administration. Plasma renin activity, vascular sensitivity to angiotensin II, and urinary excretion of the enzymes N-acetylglucosaminidase and alanineaminopeptidase were not affected by sulfinpyrazone administration. In summary, sulfinpyrazone caused a decrease of total body prostaglandin E formation in healthy female volunteers together with a moderate sodium retention. Despite inhibition of prostaglandin synthesis, glomerular filtration rate, plasma renin activity, or pressor effects of angiotensin II were not altered.