Drugs online research references
Biochem Pharmacol. 1992 Aug 18;44(4):617-20.
Catalytic activities of human debrisoquine 4-hydroxylase cytochrome P450 (CYP2D6) expressed in yeast.
Ellis SW, Ching MS, Watson PF, Henderson CJ, Simula AP, Lennard MS, Tucker GT, Woods HF.
University of Sheffield, Department of Medicine and Pharmacology, Royal Hallamshire Hospital, U.K.
A 1.57kb BamH1 fragment containing a full-length human debrisoquine 4-hydroxylase cytochrome P450 (CYP2D6) cDNA was inserted into the BglII site of the yeast expression plasmid pMA91 and the resulting recombinant plasmid, PELT1, introduced into Saccharomyces cerevisiae strain AH22. Microsomes prepared from AH22/pELT1 cells gave an absorption maximum at 448 nm and a P450 content of 67 +/- 31 pmol/mg of microsomal protein. No P450 was detectable in microsomes prepared from AH22/pMA91 control cells. A western blot of microsomes prepared from yeast transformed with pELT1 were probed with a monoclonal antibody to CYP2D6 and revealed a strong band with a molecular mass consistent with that of CYP2D6 from human liver microsomes. No corresponding band was observed with microsomes from control yeast transformed with pMA91 alone. Microsomes from AH22/pELT cells showed catalytic activity towards metoprolol (alpha-hydroxylation and O-demethylation, 0.17 and 0.78 nmol/mg protein/h, respectively); and towards sparteine (2- and 5-dehydrogenation, 1.82 and 0.59 nmol/mg protein/h, respectively). The inhibition of metoprolol metabolism by quinidine (Qd) was 200 times more potent than that of quinine (Qn), both for alpha-hydroxylation (Qd IC50 = 0.05 microM; Qn IC50 = 4 microM) and O-demethylation (Qd IC50 = 0.05 microM; Qn IC50 = 4 microM). Negligible metabolism of tolbutamide and S-mephenytoin, substrates of the 2C sub-family, and of p-nitrophenol, a substrate of CYP2E1, was detected, although a trace of the N-deethylated metabolite of lignocaine, thought to be metabolised by CYP3A4, was detected with microsomes from CYP2D6-expressing yeast cells. The results indicate that yeast cells containing human CYP2D6 cDNA express a functionally active form of the enzyme, the immunochemical and catalytic properties of which are consistent with those of human liver.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1510710&dopt=Abstract
Eur J Clin Pharmacol. 1987;32(1):71-5.
Acute haemodynamic and humoral responses to felodipine and metoprolol in mild hypertension.
Fagard R, Lijnen P, Moerman E, Staessen J, Amery A.
Oral administration of felodipine to 10 patients with mild essential hypertension acutely reduced systemic vascular resistance (SVR) by 40% after 30 min. The change in SVR was significantly related to age (r = -0.74). The reduction in the intraarterially measured brachial artery pressure was limited to 15/13 mmHg, due to a rise in cardiac output (CO). The tachycardia was sustained for 90 min, as was an elevation of plasma noradrenaline. There was a transient increase in stroke volume, associated with a reduction in pulmonary capillary wedge pressure, which was at least partly due to a reduced intravascular volume. In contrast to SVR, pulmonary vascular resistance was not affected by felodipine. Addition of intravascular metoprolol after 90 min decreased HR and CO and augmented SVR. The felodipine-induced rise in plasma renin activity (PRA) of 100% was completely reversed by metoprolol. Plasma angiotensin II (PA II) rose by 15% during felodipine, whereas plasma aldosterone concentration (PAC) was not affected. Thus, acutely administered felodipine was a potent dilator of systemic but not of pulmonary arterioles, it stimulated the sympathetic nervous system, and reduced left ventricular filling pressure. The rise in plasma renin did not result in a higher plasma aldosterone level, due partly to reduced generation of angiotensin II.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3582471&dopt=Abstract
Xenobiotica. 1988 Apr;18(4):381-7.
Differential inhibition of human liver phenacetin O-deethylation by histamine and four histamine H2-receptor antagonists.
Reilly PE, Mason SR, Gillam EM.
Department of Biochemistry, University of Queensland, St. Lucia, Australia.
1. The effects of histamine and four histamine H-2 receptor antagonists on phenacetin O-deethylation by microsomal preparations of four human livers was quantified by a radiometric-thin layer chromatographic method. 2. Histamine and three of these drugs, namely cimetidine, ranitidine and famotidine, were weak inhibitors of this cytochrome P-450-catalysed O-deethylation, but mifentidine was a potent competitive inhibitor with a Ki in the range 40-70 microM. 3. Cimetidine, histamine and mifentidine are all 4(5)-substituted imidazole derivatives, and the contrast between the very weak inhibitory effects of cimetidine and histamine, and the more potent effect of mifentidine, suggests that the imidazole moiety may play little role in the inhibition of phenacetin O-deethylase by mifentidine. 4. The demonstration that cimetidine, ranitidine and histamine were all poor inhibitors of phenacetin oxidation further suggests the possible lack of identity between the human liver cytochrome P-450 isoenzymes responsible for catalyzing the oxidation of metoprolol and phenacetin. This follows from recognizing that metoprolol oxidation is known, from both in vivo and in vitro studies, to be strongly inhibited by both of these H-2 receptor antagonists and from in vitro studies also to be inhibited by histamine.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2899931&dopt=Abstract
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