About 50% of a single bisoprolol dose is metabolized mainly by the enzyme CYP3A4 to inactive metabolites.
来源:DrugBank
代谢
... 在人类中，已知的代谢物是不稳定的或者没有已知的药理活性。 ... 福马酸比索洛尔不会被细胞色素P450 II D6（脱布里司喹羟化酶）代谢。
... In humans, the known metabolites are labile or have no known pharmacologic activity. ... Bisoprolol fumarate is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase).
The plasma concentrations and urinary excretions of bisoprolol enantiomers in four Japanese male healthy volunteers after a single oral administration of 20 mg of racemic bisoprolol were evaluated. The AUC(infinity) and elimination half-life of (S)-(-)-bisoprolol were slightly larger than those of (R)-(+)-bisoprolol in all subjects. The metabolic clearance of (R)-(+)-bisoprolol was significantly (P < 0.05) larger than that of (S)-(-)-bisoprolol (S/R ratio: 0.79+/-0.03), although the difference was small. In contrast, no stereoselective in vitro protein binding of bisoprolol in human plasma was found. An in vitro metabolic study using recombinant human cytochrome P450 (CYP) isoforms indicated that oxidation of both bisoprolol enantiomers was catalyzed by the two isoforms, CYP2D6 and CYP3A4. CYP2D6 metabolized bisoprolol stereoselectively (R > S), whereas the metabolism of bisoprolol by CYP3A4 was not stereoselective. The S/R ratio of the mean clearance due to renal tubular secretion was 0.68, indicating a moderate degree of stereoselective renal tubular secretion. These findings taken together suggest that the small differences in the pharmacokinetics between (S)-(-)- and (R)-(+)-bisoprolol are mainly due to the stereoselectivity in the intrinsic metabolic clearance by CYP2D6 and renal tubular secretion.
The pharmacokinetic properties of bisoprolol-(14)C were studied in Wistar rats, beagle dogs, and Cynomolgus monkeys. ... The metabolism of bisoprolol was studied in the same three animal species and in humans. The major metabolites are the products of O-dealkylation and subsequent oxidation to the corresponding carboxylic acids. ...
IDENTIFICATION AND USE: Bisoprolol is a beta-Adrenergic blocking agent, sometimes under the drug name Zebeta, which is indicated in the management of hypertension. It may be used alone or in combination with other antihypertensive agents. HUMAN EXPOSURE AND TOXICITY: The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. There have been at least two reported cases where a switch from propranolol to bisoprolol resulted in worsening of arrhythmia control. An elderly person died of uncontrolled bradycardia in a hospital after being mistakenly given a higher-than-prescribed dose of bisoprolol fumarate. However, it was determined that the patient had a mutation within cytochrome P2D6, which influences metabolism of the drug. ANIMAL STUDIES: Fetotoxicity in rats occurred at 125 times the maximum recommended human dose (MRHD) of bisoprolol fumarate on a body-weight-basis, and maternal toxicity occurred at 375 times the MRHD. In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day (31 times the MRHD based on body-weight), but increased early resorptions. The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays. Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice and rats. No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 123 mg/kg/day.
Bisoprolol therapy has been associated with a low rate of mild-to-moderate elevations of serum aminotransferase levels which are usually asymptomatic and transient and resolve even with continuation of therapy. There have been no well documented cases of clinically apparent, acute liver injury attributable to bisoprolol. Thus, hepatotoxicity due to bisoprolol must be very rare, if it occurs at all. Most commonly used beta-blockers have been linked to rare instances of clinically apparent liver injury, typically with onset within 2 to 12 weeks, a hepatocellular pattern of liver enzyme elevations, rapid recovery upon withdrawal, and little evidence of hypersensitivity (rash, fever, eosinophilia) or autoantibody formation.
Bisoprolol is well absorbed in the gastrointestinal tract. The AUC is 642.87 g.hr/mL and bioavailability of bisoprolol is about 90% due to the minimal first pass effects. Absorption is unaffected by food intake. Peak plasma concentrations of bisoprolol are attained within 2-4 hours and steady-state concentrations are achieved within 5 days of administration. In a pharmacokinetic study, the mean peak concentration of bisoprolol was 52 micrograms/L. Cmax at steady state concentrations of bisoprolol is 64±21 ng/ml administered at 10 mg daily.
Bisoprolol is eliminated equally by both renal and hepatic pathways. About 50% of an oral dose is excreted unchanged in the urine with the remainder of the dose excreted as inactive bisoprolol metabolites. Under 2% of the ingested dose is found to be excreted in the feces.
The volume of distribution of bisoprolol is 3.5 L/kg. The mean volume of distribution was found to be 230 L/kg in heart failure patients, which was similar to the volume of distribution in healthy patients. Bisoprolol is known to cross the placenta.
Total body clearance in healthy patients was determined to be 14.2 L/h. In patients with renal impairment, clearance was reduced to 7.8 L/h. Hepatic dysfunction also reduced the clearance of bisoprolol.
Beagles were treated with bisoprolol, a beta 1-selective adrenoceptor antagonist, for 30 days with the following daily doses: oral: 30 mg/kg; conjunctival: 0.5% solution (approx. 0.04 mg/kg) and 5% solution (approx. 0.4 mg/kg). Drug concentrations were determined in plasma and various eye tissues on days 1, 16, and 30, and on day 59, i.e. on day 29 of the follow-up period. Bisoprolol concentrations in plasma and most eye tissues were considerably higher after oral than after conjunctival treatment. The highest tissue concentrations were observed in the iris (+ciliary body) and retina (+choroid) with tissue/plasma concentration ratios between 100 and 150 after oral and 1000 to 3000 after conjunctival instillation (5% solution). In plasma no accumulation of the drug was observed which is in accordance with its plasma half-life of 4 to 5 hr. In contrast to this, concentrations in the iris and retina increased from day 1 to day 16 and 30 by 3 to 8 times and the half-life of bisoprolol in these tissues was estimated to be between 3 to 5 days.
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
申请人：BLUM Andreas
公开号：US20140135309A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I
wherein Ar, R
1
and R
2
are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014072244A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] SULFOXIMINE SUBSTITUTED PYRROLOTRIAZINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] PYRROLOTRIAZINES À SUBSTITUTION SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2015091156A1
公开（公告）日：2015-06-25
This invention relates to novel sulfoximine substituted pyrrolotriazine derivatives of formula wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1 a or MNK1 b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1 a or MNK1 b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR UNE SULFOXIMINE DESTINÉES À DES COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2015169677A1
公开（公告）日：2015-11-12
The application relates to novel sulfoximine substituted quinazoline derivatives of formula (I) wherein Ar, R1, R2 and R3 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
