Characterisation of theophylline metabolism in human liver microsomes.

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Nine healthy male volunteers were studied to assess the possibility of an interaction between theophylline and nifedipine or verapamil using axrandomised, crossover design. Subjects received theophylline 125 mg 8 hourly with and without nifedipine 20 mg 12 hourly and verapamil 80 mg 8 hourly. Nifedipine treatment reduced mean total theophylline clearance by 9%, due to decreased clearances via 1-and 3-demethylation. Verapamil treatment reduced mean total theophylline clearance by 14%, due to decreased clearances via 1-and 3-demethylation and 8-hydroxylation. Verapamil and nifedipine at usual clinical doses are unlikely to cause clinically significant changes in theophylline disposition.

Section: Discussionmentioning

confidence: 97%

Selective inhibitory effects of nifedipine and verapamil on oxidative metabolism: effects on theophylline.

Robson

Miners

Birkett

1988

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“…Microsomes were prepared from ®ve human livers (obtained from the Department of Clinical Pharmacology of Flinders Medical Centre human liver`bank') by differential centrifugation, as described previously [4]. Human kidney (sample codes HRM 0003, 0004 and 0007) and jejunum (sample codes HJM 0009, 0010 and 0011) microsomes were obtained from the International Institute for the Advancement of Medicine (Scranton, PA, USA).…”

Section: Chemicals Reagents and Human Tissue Microsomesmentioning

confidence: 99%

The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes

Bowalgaha

Miners

2001

Aims To estimate the relative contribution of liver, kidney and jejunum to MPA elimination via glucuronidation from in vitro kinetic data. Methods The kinetics of MPA glucuronidation by human liver, kidney and jejunum microsomes were characterized. Mycophenolic acid glucuronide (MPAG) concentrations in microsomal incubations were determined using a speci®c h.p.l.c. procedure. Non-speci®c microsomal binding of MPA was excluded using an equilibrium dialysis approach. Results Microsomes from all three tissues catalysed the conversion of MPA to MPAG. Mean microsomal intrinsic clearances for MPAG formation by liver, kidney and jejunum microsomes were 46.6, 73.5 and 24.5 ml (min mg) x1 , respectively. When extrapolated to the whole organ, however, hepatic intrinsic clearance was 21-and 38-fold higher than the respective intrinsic clearances for kidney and small intestine. Conclusions The data suggest that the liver is the organ primarily responsible for the systemic clearance of MPA, with little contribution from the kidney, and that the small intestine would be expected to contribute to ®rst-pass extraction to a minor extent only.

“…There is strong direct and indirect evidence that CYP1A2 is involved in all the major pathways of theophylline metabolism [6,[13][14][15][16]. The inducing effect of cigarette smoking is greatest on the two N-demethylation pathways and CYP1A2 is believed to catalyze about 80-90% of the N-demethylations and about 50% of the 8-hydroxylation in vitro [17]. There is some evidence that the remainder of the 8-hydroxylation is catalyzed by CYP2E1 and CYP3A [13].…”

Section: Introductionmentioning

confidence: 99%

Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine.

Rasmussen¹,

Mäenpää²,

Pelkonen³

et al. 1995

141

1 Fluvoxamine and seven other selective serotonin reuptake inhibitors (SRRI) were tested for their ability to inhibit a number of human cytochrome P450 isoforms (CYPs). 2 None of the drugs showed potent inhibition of CYP2A6 (coumarin 7-hydroxylase) or CYP2E1 (chlorzoxazone 6-hydroxylase), while norfluoxetine was the only 5 Ethanol inhibited the formation of 1,3-dimethyluric acid with a Ki value of 300 JM, a value which is consistent with inhibition of CYP2E1. Ethanol and fluvoxamine both inhibited 8-hydroxylation by about 45% and, in combination, the compounds decreased the formation of 1,3-dimethyluric acid by 90%, indicating that CYP1A2 and CYP2E1 are equally important isoforms for the 8-hydroxylation of theophylline. 6 It is concluded that pharmacokinetic interaction between fluvoxamine and theophylline is due to potent inhibition of CYP1A2.