Rivaroxaban, an oral, direct factor Xa inhibitor, has a dual mode of elimination in humans, with two-thirds metabolized by the liver and one-third renally excreted unchanged. P-glycoprotein (P-gp) is known to be involved in the absorption, distribution, and excretion of drugs. To investigate whether rivaroxaban is a substrate of P-gp, the bidirectional flux of rivaroxaban across Caco-2, wild-type, and P-gp-overexpressing LLC-PK1 cells was investigated. Furthermore, the inhibitory effect of rivaroxaban toward P-gp was determined. Rivaroxaban exhibited high permeability and polarized transport across Caco-2 cells. Rivaroxaban was shown to be a substrate for, but not an inhibitor of, P-gp. Of a set of potential P-gp inhibitors, ketoconazole and ritonavir, but not clarithromycin or erythromycin, inhibited Pgp-mediated transport of rivaroxaban, with half-maximal inhibitory concentration values in the range of therapeutic plasma concentrations. These findings are in line with observed area under the plasma concentration-time curve increases in clinical drug-drug interaction studies indicating a possible involvement of P-gp in the distribution and excretion of rivaroxaban. In vivo studies in wild-type and P-gp double-knockout mice demonstrated that the impact of P-gp alone on the pharmacokinetics of rivaroxaban is minor. However, in P-gp double-knockout mice, a slight increase in brain concentrations and decreased excretion into the gastrointestinal tract were observed compared with wild-type mice. These studies also demonstrated that brain penetration of rivaroxaban is fairly low. In addition to P-gp, a further transport protein might be involved in the secretion of rivaroxaban.

The pharmacokinetics of BAY 59-7939 - a novel, oral, direct Factor Xa inhibitor - were investigated in rats and dogs in support of preclinical safety studies and clinical development. BAY 59-7939 was rapidly absorbed after oral dosing, with an absolute bioavailability of 57-66% in rats, and 60-86% in dogs. Plasma pharmacokinetics of BAY 59-7939 were linear across the investigated dose range (1-10 mg kg(-1) in rats, 0.3-3 mg kg(-1) in dogs). Plasma clearance was low: 0.4 l kg(-1) h(-1) in rats and 0.3 l kg(-1) h(-1) in dogs; volume of distribution (V(ss)) was moderate: 0.3 l kg(-1) in rats, and 0.4 l kg(-1) in dogs. The elimination half-life after oral administration was short in both species (0.9-2.3 h). Whole-body autoradiography showed moderate tissue affinity. No retention or small volume enrichments of BAY 59-7939-related radioactivity were observed. The plasma-protein binding of BAY 59-7939 was high, species dependent and fully reversible. BAY 59-7939 was rapidly excreted in rats and dogs, and was not irreversibly retained. A dual mode of excretion (biliary/faecal and renal) was observed. In summary, BAY 59-7939 had a favourable, predictable pharmacokinetic profile, with high oral bioavailability and a dual route of excretion.

ABSTRACT:Sorafenib (Nexavar) is a novel oral Raf kinase and vascular endothelial growth factor receptor inhibitor. Most anticancer drugs are substrates for ATP-binding cassette efflux pumps especially for P-glycoprotein (P-gp). To evaluate the influence of P-gp on the pharmacokinetics of sorafenib substrate properties for this transporter were investigated. Therefore, permeability of sorafenib across Caco-2 and P-gp-overexpressing cells was determined. To determine the in vivo relevance of these in vitro findings, pharmacokinetics of sorafenib in mdr1a/1b(؊/؊) and wild-type (WT) mice was studied. Sorafenib is highly permeable and exhibits a slight efflux across Caco-2 cells. In P-gp-overexpressing cells, a small concentration-dependent efflux was observed, which was completely blocked by the addition of ivermectin. In mdr1a/1b(؊/؊) and WT mice, unchanged compound represented by far the majority of radioactivity in plasma. After intravenous and oral administration, brain/plasma concentration ratios in mdr1a/1b(؊/؊) mice were 1.3-to 1.5-fold higher than those in WT mice. However, after intravenous or oral administration, plasma concentrations were similar in both mouse strains. In conclusion, sorafenib is highly permeable and a weak P-gp substrate in vitro. These findings were confirmed by the small factor of 1.3 to 1.5 observed for the brain/plasma ratios in mdr1a/1b(؊/؊) versus WT mice in vivo. Based on these in vitro and in vivo results, it is unlikely that P-gp has a major effect on the plasma concentrations of sorafenib in humans. Because of the high permeability and low P-gp-mediated transport, sorafenib might be able to cross the blood-brain barrier and target tumors within the brain.

1 Recent studies demonstrated that the cardiac calpain system is activated during ischaemic events and is involved in cardiomyocyte injury. The aim of this study was to investigate the contribution of AT 1 and AT 2 receptors in the regulation of calpain-mediated myocardial damage following myocardial infarction (MI). 2 Infarcted animals were treated either with placebo, the ACE inhibitor ramipril (1 mg kg 71 d 71 ), the AT 1 receptor antagonist valsartan (10 mg kg 71 d 71 ) or the AT 2 receptor antagonist PD 123319 (30 mg kg 71 d 71 ). Treatment was started 7 days prior to surgery. On day 1, 3, 7 and 14 after MI, gene expression and protein levels of calpain I, II and calpastatin were determined in left ventricular free wall (LVFW) and interventricular septum (IS). At day 3 and 14 post MI, morphological investigations were performed. 3 Calpain I mRNA expression and protein levels were increased in IS 14 days post MI, whereas mRNA expression and protein levels of calpain II were maximally increased in LVFW 3 days post MI. Ramipril and valsartan decreased mRNA and protein up-regulation of calpain I and II, and reduced infarct size and interstitial ®brosis. PD 123319 did not a ect calpain I or II up-regulation in the infarcted myocardium, but decreased interstitial ®brosis. Calpastatin expression and translation were not a ected by AT receptor antagonists or ACE inhibitor. 4 Our data demonstrate a distinct, temporary-spatial up-regulation of calpain I and II following MI confer with the hypothesis of calpain I being involved in cardiac remodelling in the late and calpain II contributing to cardiac tissue damage in the early phase of MI. The up-regulation of calpain I and II is partly mediated via the AT 1 receptor and can be reduced by ACE inhibitors and AT 1 receptor antagonists. British Journal of Pharmacology (2001) 132, 767 ± 777 Keywords: Myocardial infarction; renin-angiotensin-system; calpain-system Abbreviations: ACE, angiotensin converting enzyme; AT 1 , angiotensin type 1 receptor; AT 2 , angiotensin type 2 receptor; [Ca 2+ ] i , intracellular calcium concentration; Calp I, calpain isoform I or m-calpain; Calp II, calpain isoform II or m-calpain; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IS, interventricular septum; LV, left ventricle; LVFW, left ventricular free wall; MAP, mean arterial blood pressure; MI, myocardial infarction; RAS, renin-angiotensin system; RV, right ventricle IntroductionThe calpain system is an intracellular, strongly Ca 2+ -dependent, neutral cysteine protease system existing in all mammalian and in some non-mammalian cells. The calpain family consists of ubiquitous and tissue speci®c isoforms of calpains and of the naturally occurring endogenous inhibitor, calpastatin. The best characterized calpains are the widely distributed isoenzymes, calpain I or m-calpain, which requires micromolar intracellular calcium ([Ca 2+ ] i )-concentrations for half-maximum activity, and calpain II or m-calpain, which requires millimolar [Ca 2+ ] i -concentrations for activation, respective...

Angiotensin II via its AT1 and AT2 receptors differentially controls transcriptional and translational regulation as well as the activity of NHE-1 and NBC-1 in the ischemic myocardium and contributes to the control of pH regulation in cardiac tissue.