Drugs online research references
Drug Metab Dispos. 2000 Nov;28(11):1327-34.
Automated definition of the enzymology of drug oxidation by the major human drug metabolizing cytochrome P450s.
McGinnity DF, Parker AJ, Soars M, Riley RJ.
Department of Physical & Metabolic Science, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom.
A fully automated assay to determine the enzymology of drug oxidation by the major human hepatic cytochrome P450s (CYPs; CYP1A2, -2C9, -2C19, -2D6, and -3A4) coexpressed functionally in Escherichia coli with human NADPH-P450 reductase has been developed and validated. Ten prototypic substrates were chosen for which clearance was primarily CYP-dependent, and the activities of these five major CYPs were represented. A range of intrinsic clearance (CL(int)) values were obtained for substrates in both pooled human liver microsomes (HLM; 1-380 microl. min(-1)mg(-1)) and recombinant CYPs (0.03-7 microl. min(-1)pmol(-1)) and thus the percentage contribution of individual CYPs toward their oxidative metabolism could be estimated. All the assignments were consistent with the available literature data. Tolbutamide was metabolized by CYP2C9 (70%) and CYP2C19 (30%), diazepam by CYP2C19 (100%), ibuprofen by CYP2C9 (90%) and CYP2C19 (10%), and omeprazole by CYP2C19 (68%) and CYP3A4 (32%). Metoprolol and dextromethorphan were primarily CYP2D6 substrates and propranolol was metabolized by CYP2D6 (59%), CYP1A2 (26%), and CYP2C19 (15%). Diltiazem, testosterone, and verapamil were metabolized predominantly by CYP3A4. In addition, the metabolite profile for the CYP-dependent clearance of several markers determined by mass spectroscopy was as predicted from the literature. There was a good correlation between the sum of individual CYP CL(int) and HLM CL(int) (r(2) = 0.8, P <.001) for the substrates indicating that recombinant CYPs may be used to predict HLM CL(int) data. This report demonstrates that recombinant human CYPs may be useful as an approach for the prediction of the enzymology of human CYP metabolism early in the drug discovery process.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11038161&dopt=Abstract
J Cardiovasc Pharmacol. 1985;7 Suppl 7:S148-53.
A comparative and long-term evaluation of ketanserin in the treatment of essential hypertension.
Hedner T, Persson B, Berglund G.
Ketanserin is a serotonin (S2) blocker that reduces blood pressure (BP) in patients with essential hypertension preferentially by a reduction of peripheral vascular resistance. Heart rate is generally not affected or slightly reduced. When given in monotherapy on a 40 mg b.i.d. regimen, ketanserin reduces diastolic BP as effectively as metoprolol 100 mg b.i.d. or hydrochlorotiazide 25 mg b.i.d. The incidence of adverse reactions is low and comparable to these reference drugs. A satisfactory BP control is provided over a 24-h interval on a 40 mg b.i.d. dosage schedule, and the effect is maintained on a long-term basis, i.e., greater than 2 years. The response seems to be more marked in older patients, which may be due to an augmented platelet serotonin release and a vascular hypersensitivity in this age group. The future usefulness of ketanserin, as well as any other antihypertensive agent, will depend on its ability to prevent organ damage, as well as its ability to provide "quality of life" for the patient.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2412038&dopt=Abstract
Res Vet Sci. 1979 Nov;27(3):372-8.
Metabolic and physiological effects of adrenoceptor agonists and antagonists in the horse.
Snow DH.
In the horse the effect of the adrenergenic agonists adrenaline, phenylephrine and salbutamol on haematocrit, plasma free fatty acid, glycerol and lactate levels were investigated. Effects on heart rate, sweating and muscle tremor were also studied. The effects of administration of the adrenoceptor antagonists propranolol, metoprolol, H35/25 and acepromazine on adrenaline-induced changes were examined. The results obtained with these agonists and antagonists suggest that the lipolysis and hyperglycaemia are mediated via beta-adrenoceptors. It appears that both beta1 and beta2 subtypes are involved. Muscle glycogenolysis, muscle tremor and sweating were mediated via beta2-adrenoceptors. Although salbutamol caused an elevation in haematocrit the other results support the alpha-mediation of adrenaline induced increases in haematocrit.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=44381&dopt=Abstract
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