Pharmacokinetic interaction between the CYP3A4 inhibitor ketoconazole and the hormone drospirenone in combination with ethinylestradiol or estradiol.

AIMS: The present study was conducted to investigate the influence of the strong CYP3A4 inhibitor ketoconazole (KTZ) on the pharmacokinetics of drospirenone (DRSP) administered in combination with ethinylestradiol (EE) or estradiol (E2). METHODS: This was a randomized, multicentre, open label, one way crossover, fixed sequence study with two parallel treatment arms. A group sequential design allowed terminating the study for futility after first study cohort. About 50 healthy young women were randomized 1 : 1 to 'DRSP/EE' or 'DRSP/E2'. Subjects in the 'DRSP/EE' group received DRSP 3 mg/EE 0.02 mg (YAZ®, Bayer) once daily for 21 to 28 days followed by DRSP 3 mg/EE 0.02 mg once daily plus KTZ 200 mg twice daily for 10 days. Subjects in the 'DRSP/E2' group received DRSP 3 mg/E2 1.5 mg (research combination) once daily for 21 to 28 days followed by DRSP 3 mg/E2 1.5 mg once daily plus KTZ 200 mg twice daily for 10 days. RESULTS: Oral co-administration of DRSP/EE or DRSP/E2 and KTZ resulted in an increase in DRSP exposure (AUC(0,24 h)) in both treatment groups: DRSP/EE group: 2.68-fold DRSP increase (90% CI 2.44, 2.95); DRSP/E2 group: 2.30-fold DRSP increase (90% CI 2.08, 2.54). EE and estrone (metabolite of E2) exposures were increased ~1.4-fold whereas E2 exposure was largely unaffected by KTZ co-administration. CONCLUSIONS: A moderate pharmacokinetic drug-drug interaction between DRSP and KTZ was demonstrated in this study. No relevant changes of medical concern were detected in the safety data collected in this study.

Pharmacokinetics and imaging properties of Gd-EOB-DTPA in patients with hepatic and renal impairment.

OBJECTIVES: : The purpose of this study was to determine the pharmacokinetics (PKs), imaging properties, and safety of the liver-specific magnetic resonance (MR) imaging contrast agent gadoxetic acid disodium (Gd-EOB-DTPA) in subjects with various levels of hepatic impairment, renal impairment, or coexisting hepatic and renal impairment. MATERIALS AND METHODS: : In this single-center, open-label, parallel-group study, patients with varying degrees of renal and/or hepatic impairment were compared with healthy subjects matched for age, gender, and weight (control group). All subjects received a single intravenous bolus of Gd-EOB-DTPA (Primovist, Eovist, EOB-Primovist) 25 µmol/kg body weight. Samples of serum, urine, and feces were collected for PK analysis. MR imaging was performed before dosing and at preset times after dose administration to determine enhancement relative to predose signal intensity values. Safety was assessed by monitoring adverse events, laboratory values, vital signs, cardiac rhythm, oxygen saturation, and by physical examination findings. RESULTS: : Gd-EOB-DTPA was well tolerated by all subjects. Total clearance of Gd-EOB-DTPA did not significantly change in patients with mild and moderate hepatic impairment (Child-Pugh A and B), compared with the control group. Mean urinary excretion was increased and mean fecal excretion was decreased in patients with hepatic impairment. Renal excretion was increased to between 72% and 96% of the dose administered in patients with very high bilirubin levels (>3 mg/dL), compared with 48% in the control group. Total clearance of Gd-EOB-DTPA was significantly reduced to 140 ± 45 mL/min and terminal elimination half-life (t1/2) was slightly, but not significantly, increased to 2.6 ± 0.9 hours in patients with severe hepatic impairment (Child-Pugh C), compared with the control group (209 ± 37 mL/min and 1.8 ± 0.2 hours, respectively). Liver MR signal enhancement (area under the curve of relative enhancement [%] over time) was similar in patients with mild and moderate hepatic impairment and in those in the control group, but was decreased by 38% in patients with severe hepatic impairment, compared with control. Peak liver enhancement, however, was still at a high level (118% ± 57%). PK and imaging parameters were not significantly affected in patients with moderate renal impairment (creatinine clearance, 30-50 mL/min). In patients with end-stage renal failure (ESRF), however, the PK profile of Gd-EOB-DTPA was significantly different, with an increased t1/2 (20.0 ± 7.0 hours vs. 1.8 ± 0.2 hours in the control group). During a 3-hour dialysis session that started 1 hour after administration of the intravenous dose, the serum levels in patients with ESRF declined by between 71% and 88% as a result of elimination by hemodialysis and parallel hepatobiliary excretion. This is comparable with the decline observed in healthy subjects (85%) during the 1- to 4-hour interval after injection. CONCLUSIONS: : The results of the present study show that in humans with moderate renal impairment and mild-to-moderate hepatic impairment, no relevant changes in PK parameters, such as total clearance and t1/2, develop as a result of increased renal excretion to compensate in the case of hepatic impairment (or increased hepatic elimination in the case of renal impairment). The t1/2 of Gd-EOB-DTPA was markedly altered only in patients with ESRF. The high MR signal enhancement profile, observed even in patients with severe hepatic impairment, indicates that there is no need to adjust the dose of Gd-EOB-DTPA.

Improved characterization of focal liver lesions with liver-specific gadoxetic acid disodium-enhanced magnetic resonance imaging: a multicenter phase 3 clinical trial.

OBJECTIVES: To evaluate the safety of gadoxetic acid disodium (Gd-EOB-DTPA) magnetic resonance imaging (MRI) and its efficacy in characterizing liver lesions. METHODS: Lesion characterization and classification using combined (unenhanced and Gd-EOB-DTPA-enhanced) MRI were compared with those using unenhanced MRI and contrast-enhanced spiral computed tomography (CT) using on-site clinical and off-site blinded evaluations for patients with focal liver lesions. RESULTS: Gadoxetic acid disodium was well tolerated in this study. For the clinical evaluation, more lesions were correctly characterized using combined (unenhanced and Gd-EOB-DTPA-enhanced) MRI than using unenhanced MRI and spiral CT (96% vs 84% and 85%, respectively; P < or = 0.0008). For the blinded evaluation, more lesions were correctly characterized using combined MRI compared with using unenhanced MRI (61%-76% vs 48%-65%, respectively; P < or = 0.0012 for 2/3 readers); when compared with spiral CT, a similar proportion of lesions were correctly characterized. CONCLUSIONS: Gadoxetic acid disodium-enhanced MRI is of clinical benefit relative to unenhanced MRI and spiral CT for a radiological diagnosis of liver lesions.

Enhancement of liver parenchyma after injection of hepatocyte-specific MRI contrast media: a comparison of gadoxetic acid and gadobenate dimeglumine.

PURPOSE: To compare enhancement of liver parenchyma in MR imaging after injection of hepatocyte-specific contrast media. MATERIALS AND METHODS: Patients (n = 295) with known/suspected focal liver lesions randomly received 0.025 mmol gadoxetic acid/kg body weight or 0.05 mmol gadobenate dimeglumine/kg body weight by means of bolus injection. MR imaging was performed before and immediately after injection, and in the delayed phase at approved time points (20 min after injection of gadoxetic acid and 40 min after injection of gadobenate dimeglumine). The relative liver enhancement for the overall population and a cirrhotic subgroup was compared in T1-weighted GRE sequences. An independent radiologist performed signal intensity measurements. Enhancement ratios were compared using confidence intervals (CIs). RESULTS: The relative liver enhancement in the overall population was superior with gadoxetic acid (57.24%) versus gadobenate dimeglumine (32.77%) in the delayed-imaging phase. The enhancement ratio between the contrast media was statistically significant at 1.75 (95% CI: 1.46-2.13). In the delayed phase, the enhancement of cirrhotic liver with gadoxetic acid (57.00%) was comparable to that in the overall population. Enhancement with gadobenate dimeglumine was inferior in cirrhotic liver parenchyma (26.85%). CONCLUSION: In the delayed, hepatocyte-specific phase, liver enhancement after injection of gadoxetic acid was superior to that obtained with gadobenate dimeglumine.

Short-term treatment with a beta-blocker with vasodilative capacities improves intrarenal endothelial function in experimental renal failure.

AIMS: In patients with renal disease the cardiovascular risk is greatly increased, and endothelial dysfunction is assumed to play a pivotal role in this process. Therefore we compared treatment effects of a beta-blocker with additional vasodilatory capacities (nebivolol) and a beta-blocker lacking these actions (metoprolol) on intrarenal and coronary vascular function in a rat model of renal failure with hypertension. MAIN METHODS: Renal failure was induced by 5/6-nephrectomy (Nx) and analyzed after 4 weeks in Wistar rats. Untreated Nx, Nx/nebivolol 6 mg/d (Nx-Nebi); Nx/metoprolol 60 mg/d (Nx-Meto) and sham-operated (Sham) animals were studied. Isolated small renal and coronary arteries were investigated for endothelium-dependent relaxation to acetylcholine (ACh) and for the contribution of the endothelial mediators NO and endothelium-derived hyperpolarizing factor (EDHF). KEY FINDINGS: Systolic blood pressure (SBP) was significantly increased in Nx, Nx-Nebi, and Nx-Meto (168+/-5, 153+/-3, and 162+/-6 mmHg) compared to Sham (138+/-3 mmHg, p<0.05, respectively). The increase in albuminuria of Nx (120-fold vs. Sham, p<0.0001) was almost (-85%) normalized by nebivolol compared to Sham (p<0.05), whereas metoprolol induced no significant effect. Renal arteries showed significantly increased Ach-relaxation in Nx and Nx-Nebi (Emax 86+/-4% and 76+/-7%, p<0.05) due to an increase in EDHF-mediated dilation (Emax_EDHF 78+/-7% and 73+/-6%) compared to Sham (Emax 54+/-4% and Emax_EDHF 44+/-6%) and Nx-Meto (Emax 42+/-12% and Emax_EDHF 18+/-5%). ACh-relaxation in coronary arteries was similar between groups but the contribution of NO (relative to EDHF) was strongly increased by nebivolol. SIGNIFICANCE: The present findings offer an explanation of the nephroprotective effect of intrarenal endothelial function in renal failure.

Low sodium modifies the vascular effects of angiotensin-converting enzyme inhibitor therapy in healthy rats.

Low dietary sodium (LS) increases the effect of angiotensin-converting enzyme (ACE) inhibitor therapy in patients and experimental models, but mechanisms underlying this enhanced efficacy are largely unknown. Because the benefits of ACE inhibition are mediated to a considerable extent by their effect on the vasculature, we studied whether low sodium alters the vascular effects of ACE inhibition. Baseline functional and morphological characteristics, and endothelium-dependent and -independent dilatory responses were studied in isolated perfused small intrarenal and mesenteric arteries obtained from control rats (CON), rats on LS, lisinopril-treated rats (CON-LIS), or rats treated with lisinopril during LS (LS-LIS). We found, first, that LS-LIS compared with CON-LIS enhances blood pressure reduction. Second, interlobar renal arteries had increased lumen diameter and reduced adrenergic contractility in CON-LIS compared with CON, without additional effects of LS. In contrast, mesenteric arteries were not altered in CON-LIS compared with CON, but became triggered for increased myogenic and adrenergic constriction in LS-LIS. Third, LS-LIS decreased acetylcholine (ACh)-induced vasodilation in both mesenteric and renal arteries compared with CON-LIS. During the latter condition, opposite prostaglandins are involved in the endothelial function of the two different vascular beds, i.e., increased involvement of contractile prostaglandins in ACh-induced vasodilatation in renal arteries, versus dilatory prostaglandins in mesenteric arteries. Whether cause or consequence of the enhanced blood pressure response, our data demonstrate a modifying effect of dietary sodium on vascular effects of ACE inhibition. These findings provide a rationale for further studies addressing the mechanism-of-actions of our therapies to find additional strategies to improve therapy response.

High dietary sodium blunts affects of angiotensin-converting enzyme inhibition on vascular angiotensin I-to-angiotensin II conversion in rats.

High sodium intake blunts the efficacy of angiotensin (Ang)-converting enzyme (ACE) inhibition (ACEi), but the underlying mechanism is incompletely characterized. High sodium has been reported to increase vascular expression and vascular activity of ACE. To investigate whether high-dietary sodium-induced effects on vascular conversion of Ang I might be involved in the sodium-induced blunting of the response to ACEi, the authors studied the vasoconstrictor responses to Ang I and Ang II of isolated aortic rings from healthy rats on low dietary sodium (LS: 0.05% NaCl) and high dietary sodium (HS: 2.0% NaCl) after 3 weeks of ACEi (lisinopril 75 mg/L) or vehicle (CON). Blood pressure was similar in LS and HS in CON, but HS blunted the blood pressure response to ACEi. Functional conversion of Ang I was assessed as the difference in dose-response curves to Ang I and Ang II in parallel aortic rings. Sodium intake did not affect the dose-response curves to Ang I and Ang II in CON. In the ACEi groups, a significant difference was present between the curves for Ang I and Ang II on LS (deltaEC50, 6.7 nM; range, 2.2-13 nM; P < 0.01) but not on HS (deltaEC50: 1.3 nM; range, 0.0-4.1 nM, median [interquartile range], NS). Thus, HS blunts the ACEi-induced reduction of functional vascular Ang I conversion compared with LS. Whether the blunted functional vascular conversion is causally related to the blunted blood pressure response remains to be elucidated.

Coronary myogenic constriction antagonizes EDHF-mediated dilation: role of KCa channels.

In hypertension, pressure-induced myogenic constriction and impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation may contribute to increased vasomotor tone. Myogenic constriction as well as EDHF-mediated dilation may share common signaling mechanisms, and both may control KCa channel activity to set arterial tone. To investigate a potential relation between the 2 mechanisms, we studied coronary arteries of Sprague-Dawley rats for individual myogenic constriction compared with EDHF-mediated dilation of the same artery. EDHF-mediated dilation was measured as the maximal dilation to acetylcholine (100 micromol/L) after preconstriction, resistant to NO inhibition (NG-methyl-l-arginine acetate salt, L-NMMA, 100 micromol/L), and prostaglandin inhibition (indomethacin, 10 micromol/L) but abolished by charybdotoxin (100 nmol/L) plus apamin (500 nmol/L). Individual coronary myogenic constriction at an intraluminal pressure of 70 mm Hg (n=9) ranged from 6% to 44% (24+/-4%). EDHF-mediated dilation ranged from 18% to 84% (42+/-7%). Elevating pressure to 130 mm Hg (n=8) increased myogenic constriction by 2-fold (P<0.01) and decreased EDHF-mediated dilation by 2.6-fold (P<0.01). Interestingly, individual myogenic constriction inversely correlated to individual EDHF-mediated dilation (r=-0.75, P<0.001, n=17). Pretreatment with the KCa channel opener NS1619 (30 micromol/L) prevented coronary myogenic constriction and increased EDHF-mediated dilation by 2.2-fold (P<0.01), whereas the KATP channel opener cromakalim (3 micromol/L) had no effect on EDHF-mediated dilation. For comparison, in mesenteric arteries (at 70 mm Hg) low myogenic constriction (2+/-1%) was associated with high EDHF-mediated dilation (93+/-2%), and pretreatment with NS1619 had no effect. Our results demonstrate that myogenic constriction in coronary arteries antagonizes EDHF-mediated dilation. Activation of KCa channels with NS1619 reduces myogenic constriction and profoundly increases EDHF-mediated dilation, specifically in coronary arteries, suggesting a potential therapeutic impact to reduce coronary risk in hypertension.

Endothelial dysfunction and infarct-size relate to impaired EDHF response in rat experimental chronic heart failure.

BACKGROUND: The rat coronary ligation model of chronic heart failure has been extensively used to investigate its pathophysiology including the role of endothelial dysfunction. Inconsistent results have been obtained concerning the role of endothelial dilative mediators nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). AIMS: Our aim was to investigate involvement of NO and EDHF in aortic endothelial dysfunction in this model and the influence of individual infarct sizes. Furthermore, we investigated whether it is justified to regard rats that failed to develop large infarct sizes as SHAM controls. METHODS: We performed coronary ligations and SHAM operations and studied acetylcholine (ACh)-induced relaxations and underlying endothelial mediators in isolated aortic rings 12 weeks after infarction. By then, cardiac and hemodynamic parameters were deteriorated in animals with large myocardial infarctions (large-MI, 35+/-3%), but not those with small myocardial infarctions (small-MI, 5+/-2%). RESULTS: Large-MI showed decreased ACh-induced relaxation compared to SHAM due to decreased contribution of EDHF which was inversely correlated with individual infarct-size. Interestingly, small-MI showed significantly increased ACh-induced relaxation compared to SHAM due to increased NO contribution. CONCLUSIONS: Our results suggest that impaired aortic endothelial dilatory function in large-MI is mainly due to an impaired EDHF response and strongly depends on individual infarct-size. In addition, endothelium-dependent relaxation of small-MI rats differed from SHAM, indicating that both groups may not be pooled to serve as controls. These results emphasize the importance of infarct-size and choice of the control group, and may explain inconsistencies in previous studies.

Endothelial dilatory function predicts individual susceptibility to renal damage in the 5/6 nephrectomized rat.

In experimental animal models of renal disease the degree of renal damage varies between individuals. This could be caused by variation in the noxious event or by differences in individual susceptibility. Intact endothelial function is assumed to provide a defense mechanism against progressive renal damage. This study hypothesized that interindividual differences in renal endothelial function might be involved in individual susceptibility to renal damage, and it investigated whether endothelial function of small renal arteries before induction of 5/6 nephrectomy (5/6 Nx) in rats was related to development of renal damage after 5/6 Nx. Wistar rats underwent 5/6 Nx, and small renal arteries of the removed right kidney were investigated for endothelium-dependent relaxation to acetylcholine (ACh, 10(-8) to 10(-4) mol/L). The contribution of underlying endothelial dilative mediators, NO, prostaglandins (PG), and endothelium-derived hyperpolarizing factor (EDHF), was assessed using the inhibitors, L-NMMA, indomethacin, and charybdotoxin+apamin, respectively. After 5/6 Nx, proteinuria developed in each rat ranging from 22 to 278 (84 +/- 14) mg/24 h at week 5 (n = 23). Interestingly, a significant inverse correlation between individual ACh-relaxation (expressed as area under curve in arbitrary units) and proteinuria 5 wk after 5/6 Nx was found (r = -0.54; P = 0.008; n = 23). An inverse correlation was also found between individual NO contribution as well as PG contribution and proteinuria 5 wk after 5/6 Nx (r = -0.86, P = 0.001, n = 11; and r = -0.74, P = 0.01, n = 11, respectively). In addition, individual ACh-relaxation was positively correlated with GFR measured 6 wk after 5/6 Nx (r = 0.58; P = 0.016; n = 17). This study demonstrates for the first time that individual renal endothelial dilatory function of the healthy rat predicts susceptibility to renal damage after 5/6 Nx, which seems to depend on individual endothelial NO and PG activity.

Impaired coronary endothelial function in a rat model of spontaneous albuminuria.

BACKGROUND: Albuminuria is an independent risk factor of coronary artery disease and has been proposed to reflect a general endothelial disorder. The Munich Wistar Frömter (MWF) rat strain develops spontaneous albuminuria and, therefore, may be an interesting experimental model to study alterations of endothelial function under conditions of increased albuminuria. Our aim was to investigate if the MWF strain shows generalized endothelial dysfunction or endothelial dysfunction localized to the coronary vascular bed, and if so, determine which endothelial dilative mediators are involved. METHODS: Coronary and mesenteric arteries were investigated for endothelium-dependent relaxation and the contribution of prostacyclin, nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) in MWF rats compared to normal Wistar rats. In addition, as MWF rats show increased blood pressure, spontaneously hypertensive rats (SHR) with similar hypertension but without increased albuminuria also were studied. RESULTS: Maximal total endothelium-dependent relaxation of coronary arteries was strongly impaired in MWF rats (55 +/- 3%) compared to Wistar (89 +/- 5%) and SHR (89 +/- 2%) P < 0.05, respectively. The NO-mediated relaxation as well as the relaxation mediated by EDH were significantly lower in coronary arteries from MWF compared to Wistar. In mesenteric arteries of MWF the endothelium-dependent relaxation was intact. CONCLUSIONS: The strong impairment of coronary endothelium-dependent relaxation in the MWF model of spontaneous albuminuria may be due to defects in production or activity of NO and EDH. The intact mesenteric endothelium-dependent relaxation suggests that increased albuminuria may not be related to generalized endothelial vasodilator dysfunction in this model. Selective impairment of coronary endothelial function in a setting of spontaneous albuminuria may be a feature of the MWF that may be employed to further study cause-effect relations between albuminuria and coronary artery disease.