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Keywords: Propiverine; extended release; circadian rhythm; ABCC2 570 Pharmacokinetics and PharmacodynamicsDisposition and Antimuscarinic Effects of the Urinary Bladder Spasmolytics Propiverine: Influence of Dosage Forms and Circadian-Time Rhythms SAGE Publications, Inc.200810.1177/0091270008315314 [...]

This open-label, randomized, 3-period crossover study evaluated the pharmacokinetic interaction potential of roflumilast and budesonide following repeated coadministration to healthy male subjects (N = 12). Treatments consisted of oral roflumilast [...]

Increased synthesis rate of fibrinogen, an independent risk factor for cardiovascular disease, was recently reported in obese insulin-resistant female adolescents with chronic elevated nonesterified fatty acids (NEFA). It is unknown whether a short-term change of NEFA concentrations controls hepatic fibrinogen synthesis. Therefore, 10 healthy male volunteers (24.5 [+ or -] 3.3 yr, body mass index 23.5 [+ or -] 2.9 kg/[m.sup.2]) were investigated in random order under basal and elevated NEFA for 8 h. Leucine metabolism, the fractional synthesis rates (FSR) of plasma fibrinogen, and endogenous urea production rates were measured during primed, continuous infusion of [1-[sup.13]C]leucine and [[sup.15][N.sub.2]] urea, respectively. Plasma [alpha]-[[sup.13]C]ketoisocaproic acid and [[sup.15][N.sub.2]]urea enrichment values were measured with GC-MS. Plasma fibrinogen was isolated with the [beta]-alanine method, and fibrinogen-related [[sup.13]C]leucine enrichment was analyzed by GC-C-IRMS. Lipofundin infusion and subcutaneous heparin tripled NEFA and triglycerides in the tests. Plasma glucose, circulating insulin, human C-peptide, and plasma glucagon were not changed by the study procedure. Fibrinogen FSR were significantly lower in tests with NEFA elevation (18.44 [+ or -] 4.67%) than in control tests (21.48 [+ or -] 4.32%; P < 0.05). Plasma fibrinogen concentrations measured were not significantly different (NEFA test subjects: 1.85 [+ or -] 0.33, controls: 1.97 [+ or -] 0.54 g/l). Parameters of leucine metabolism, such as leucine rate of appearance, leucine oxidation, and nonoxidative leucine disposal, were not influenced by NEFA elevation, and endogenous urea production remained unchanged. NEFA contributes to short-term regulation of fibrinogen FSR in healthy volunteers under unchanged hormonal status, leucine metabolism, and overall amino acid catabolism. Its contribution might be of relevance at least after fat-rich meals, counteracting by reduction of FSR the blood viscosity increase implied by hyperlipidemia. stable isotopes; fatty acids; leucine metabolism; urea production

Background: In a recently described probe drug cocktail for clinically relevant drug transporters containing digoxin, furosemide, metformin and rosuvastatin, mutual interactions were essentially absent except for increases in the systemic exposure of rosuvastatin. To optimize the cocktail, we further examined the dose dependence of the effects of metformin and furosemide on rosuvastatin pharmacokinetics.Methods: This was a randomized, open label, single center, six-treatment, six-period, six-sequence crossover trial. Eighteen healthy male subjects received 10 mg rosuvastatin as reference treatment and, as test treatments, 10 mg rosuvastatin combined with 10, 50 or 500 mg metformin (T1, T2 and T3) or with 1 or 5 mg furosemide (T4 and T5). Primary pharmacokinetic endpoints were rosuvastatin Cmax (maximum plasma concentration) and AUC0–tz (area under the plasma concentration–time curve from time zero to the last quantifiable concentration).Results: The relative bioavailability of rosuvastatin was essentially unchanged when administered with metformin in T1 and T2, but in T3 it increased to 152% for AUC0–tz (90% CI 135–171%) and 154% for Cmax (90% CI 132–180%). Coadministration with furosemide did not change rosuvastatin relative bioavailability in T4, but in T5 it increased slightly to 116% for AUC0–tz (90% CI 102–132%) and 118% for Cmax (90% CI 98–142%).Conclusion: The increased systemic exposure of rosuvastatin when administered as part of the proposed transporter cocktail is most likely attributable to metformin and only to a minor degree to furosemide. Reduction of the doses of metformin and furosemide is expected to eliminate the previously described interaction.EudraCT no. 2015-003052-46, ClinicalTrials.gov identifier NCT02574845. [ABSTRACT FROM AUTHOR]

Background and Aims: The disposition and sterol-lowering effect of ezetimibe are associated with long-lasting enterosystemic circulation, which is initiated by secretion of ezetimibe and its glucuronide via intestinal P-glycoprotein (P-gp) (ABCB1) and the multidrug resistance-associated protein 2 (MRP2) (ABCC2) into gut lumen. Hepatic uptake and secretion may contribute to recycling. To obtain deeper insight into the intestinal and hepatic processes, the disposition of ezetimibe was studied in the presence of rifampin (INN, rifampicin), a modulator of P-gp, MRP2, and hepatic organic anion (uptake) transporting polypeptides (OATPs) (SLCOs).Methods: The disposition of ezetimibe (20 mg orally) alone and after coadministration of rifampin (600 mg orally) was measured in a crossover study of 8 healthy subjects with the SLCO1B1 *1a/*1a genotype. Concentrations of ezetimibe and its glucuronide in serum, urine, and feces, as well as cholesterol, lathosterol, and the plant sterols campesterol and sitosterol in serum, were quantified by use of liquid chromatography and gas chromatography with mass spectrometric detection.Results: After rifampin administration, the maximum serum concentrations of ezetimibe and its glucuronide were significantly elevated (12.0 ± 4.20 ng/mL versus 4.67 ± 2.72 ng/mL, P = .017, and 282 ± 73.8 ng/mL versus 107 ± 35.3 ng/mL, P = .012, respectively). The area under the curve of ezetimibe was not affected (102 ± 37.6 ng · h/mL versus 140 ± 86.3 ng · h/mL, P = not significant), whereas that of the glucuronide was markedly increased (2150 ± 687 ng · h/mL versus 1030 ± 373 ng · h/mL, P = .012). Renal clearance remained unchanged. Fecal excretion of ezetimibe was markedly decreased (7.6 ± 2.2 mg versus 10.4 ± 1.8 mg, P = .036), whereas renal excretion of the glucuronide was strongly elevated (4.8 ± 1.9 mg versus 2.0 ± 1.2 mg, P = .049) after coadministration. The onset of a significant sterol-lowering effect of ezetimibe was significantly shortened by rifampin coadministration.Conclusions: Coadministration of rifampin increases the maximum serum concentrations of ezetimibe but reduces its enterosystemic recycling, most likely by inhibition of the secretion of ezetimibe and its glucuronide via P-gp and MRP2.Clinical Pharmacology & Therapeutics (2006) 80, 477–485; doi: 10.1016/j.clpt.2006.07.006 [ABSTRACT FROM AUTHOR]