Bioavailability of opipramol from a film-coated tablet, a sugar-coated tablet and an aqueous solution in healthy volunteers.

Opipramol (4-[3-(5H-dibenz[b,f]-azepine-5-yl)-propyl]-1-piperazine-ethanol dihydrochloride, CAS 315-72-0) is regarded as an anxiolytic compound with antidepressant properties, and it is one of the most frequently prescribed psychotropic drugs in Germany. In two open, randomized cross-over studies in 20 (study 1) and 18 (study II) healthy volunteers, the relative bioavailability of 50 mg opipramol-2HCl from a sugar-coated tablet was compared with an aqueous solution, and of 100 mg opipramol-2HCl from a newly developed film-coated tablet was compared with the sugar-coated tablet. The concentrations of opipramol were determined in plasma by high-performance liquid chromatography (HPLC) with photometric detection. The mean dose corrected kinetic parameters of opipramol were similar after administration of all formulations. The peak concentrations of opipramol were 13-15 ng ml-1 (study I) and 28 ng ml-1 (study II). They were achieved after 3 h. The area under the plasma concentration-time curve was about 170 ng ml-1 h (study I) and about 320 ng ml-1 h (study II). The terminal plasma half-life was 11 h. Bioequivalence was proven between sugar-coated tablet and aqueous solution, and between film-coated tablet and sugar-coated tablet, respectively. In addition, in study II the plasma concentrations and pharmacokinetic parameters of the metabolites opipramol N-oxide and deshydroxyethyl opipramol were determined.

Cyclo-oxygenase-2 inhibition increases blood pressure in rats.

1 It is known that nonselective cyclo-oxygenase (COX) inhibitors have small but significant effects on blood pressure (BP), most notably in hypertensive patients on antihypertensive medication. Whether selective COX-2 inhibitors also interfere with BP regulation is not well understood. Therefore, we aimed to examine the effect of chronic treatment with a selective COX-2 inhibitor (rofecoxib) on systolic blood pressure (sBP) in normotensive Wistar-Kyoto rats (WKY) and on the developmental changes of sBP in young spontaneously hypertensive rats (SHR). In addition, we investigated a possible influence of salt intake on the effects of COX-2 inhibition on BP in these two rat strains. 2 Rofecoxib dose dependently increased sBP and decreased plasma levels of 6-keto prostaglandin (PG)F(1alpha) in WKY rats fed a normal salt diet (0.6% NaCl, wt wt(-1)), without affecting serum thromboxane (TX)B(2) levels. 3 Rofecoxib significantly elevated sBP in both rat strains fed normal salt or high salt diet (8% NaCl, wt wt(-1)), but not in rats on low salt intake (0.02% NaCl, wt wt(-1)). 4 Rofecoxib significantly decreased plasma levels of 6-keto PGF(1alpha) in both rat strains fed normal or high salt diet, but not in rats during low salt intake. 5 Rofecoxib exerted no influence on the changes of body weight nor on water intake. Plasma renin activity (PRA) and renocortical renin mRNA abundance were not changed by rofecoxib, but plasma aldosterone concentration (PAC) was significantly reduced. 6 These results suggest that chronic inhibition of COX-2 causes an increase of blood pressure that depends on prostacyclin synthesis. Furthermore, this increase is independent on genetic predisposition and can be prevented by salt deprivation. Since water intake and body weight gain were not changed by rofecoxib, fluid retention appears not to be a major reason for the development of hypertension. Similarly, an activation of the renin-angiotensin-aldosterone axis appears to be an unlikely candidate mechanism.

Role of prostanoids in regulation of the renin-angiotensin-aldosterone system by salt intake.

We investigated the effect of cyclooxygenase (COX) activity on the regulation of the renin-angiotensin-aldosterone system by salt intake. Therefore, Sprague-Dawley rats were subjected to different salt diets [0.02, 0.6, and 8% NaCl (wt/wt)] and treated with the selective COX-2 inhibitor rofecoxib (10 mg x kg body wt(-1) x day(-1)) or with ketorolac at a dose selective for COX-1 inhibition (2 mg x kg body wt(-1) x day(-1)) for 3, 7, 14, and 21 days. Rofecoxib and ketorolac caused a similar reduction of renocortical PGE2 formation with a low-salt diet. Rofecoxib did not change plasma renin activity or renocortical renin mRNA abundance with any of the diets but clearly lowered plasma aldosterone concentration. In contrast, ketorolac delayed the increase in plasma renin activity and of renin mRNA in response to low salt intake but did not change plasma aldosterone concentration. Prolonged treatment with rofecoxib but not with ketorolac caused an upregulation of COX-2 expression while COX-1 mRNA abundance remained unchanged. These findings suggest that COX-1-derived, but not COX-2-derived, prostanoids are of relevance for the regulation of the renin system by salt intake.

Comparison of bioavailability and metabolism with two commercial formulations of cyclosporine a in rats.

The bioavailability and metabolism of cyclosporine A (CsA) capsules were compared with two bioequivalent (Food and Drug Administration approved) preparations in rats. Two groups of Wistar-Kyoto rats were given 10 mg/kg q.d. of Sandimmun Neoral (NEO), Novartis Pharma, and CsA (United States Pharmacopeia modified), Eon Labs (EON), as capsules dissolved in water by oral gavage. After reaching steady-state (SS), rats were euthanized 2, 4, 8, 12, and 24 h after dosing. Parallel to this investigation, a single dose (SD) study was also performed. CsA and CsA metabolite concentrations of AM1, AM4N, and AM9 were determined by high-performance liquid chromatography in kidney, whole blood, and urine. The bioavailability of EON was 15% lower [area under the curve (AUC)(SS blood CsA), 27.9 +/- 3.69 mg. h/l] in the blood and was 40% lower (AUC(SS kidney CsA), 136.2 +/- 21.2 mg. h/l) in the kidney in contrast to NEO (AUC(SS blood CsA), 32.1 +/- 4.32 mg. h/l and AUC(SS kidney CsA), 220.8 +/- 29.5 mg. h/l). In contrast, the plasma AM4N level was significantly elevated in group receiving EON (AUC(SS blood AM4N), 4.1 +/- 0.42 mg. h/l) compared with the other group treated with NEO (AUC(SS blood AM4N), 2.9 +/- 0.39 mg. h/l). In the kidneys, no significant differences were observed concerning the AM4N concentrations of NEO (AUC(SS kidney AM4N), 11.8 +/- 1.87 mg. h/l) versus EON (AUC(SS kidney AM4N), 12.1 +/- 2.14 mg. h/l), but AM1 was increased (AUC(SS kidney AM1), 54.3 +/- 11.2 mg. h/l) in comparison to NEO (AUC(SS kidney AM1), 20.5 +/- 3.56 mg. h/l). Furthermore, EON produced a larger amount of AM4N in the urine (5.8 +/- 0.85 mcirog/24 h versus 2.2 +/- 0.95 microg/24 h). Similar results were obtained with the SD study. Although the clinical consequences of our results remain at present unknown, the data suggest differences in CsA disposition that may affect drug efficacy and safety and merit further investigation in humans.