In vivo Evidence that Theophylline Is Metabolized Principally by CYP1A in Rats

Bachmann, Kenneth; Sanyal, Gaurab; Potter, Jeffrey; Schiavone, Robert; Loch, Janette M.

doi:10.1159/000139071

Cited by 15 publications

(10 citation statements)

References 17 publications

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“…linear kinetics at the dosages used and minimum influence of protein binding on probe kinet ics. The utility of theophylline as a probe for CYP1A activity in rats has been reported [17]. Gu et al [18] reported that theophylline is principally oxidized by human CYP1A2.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Anesthetic Agents on Rat Hepatic Cytochromes P450 in vivo

Loch

Potter

Bachmann³

1995

Pharmacology

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The objective of this study was to identify which anesthetics when used acutely will affect cytochrome P450 (CYP) activity in male Sprague-Dawley rats in vivo. The anesthetics tested were fentanyl citrate, α-chloralose, ketamine, urethane (ethyl carbamate), halothane, and ether. CO₂ anesthesia was used as the control comparator. Theophylline was used as a probe for CYP1A activity, phenobarbital for CYP2B/2C, flecainide for CYP2D1, and ethosuximide for CYP 3A activity. All probes were administered via tail vein injection after anesthetic-induced loss of the righting reflex. Single sample probe clearances were estimated, and used as an index of CYP activity. Fentanyl citrate, α-chloralose, halothane, and ether did not have statistically significant effects on any of the CYP activities. Ketamine did not significantly affect CYP1 or CYP2B/ 2C activity. However, it decreased the clearance of flecainide (i.e. CYP2D1 activity) by 13.4% (p < 0.001) and the clearance of ethosuximide (i.e. CYP3A activity) by 17.6% (p < 0.0001). Urethane increased the clearance of theophylline by 91.5% (p < 0.0001), and decreased the clearance of ethosuximide by 40.5% (p < 0.0001) though it did not affect CYP2B/2C or CYP2D1 activities significantly. From this data, we conclude that a single dose of ketamine mildly inhibits the activity of CYP2D1 and CYP3A, and a single dose of urethane strongly inhibits CYP3A but increases CYP1A activity.

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Section: Discussionmentioning

confidence: 99%

The Influence of Anesthetic Agents on Rat Hepatic Cytochromes P450 in vivo

Loch

Potter

Bachmann³

1995

Pharmacology

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“…Twenty male Sprague-Dawley rats were randomly divided into four groups (n=5 rats each). During the morning of the experiment, PRN (5 mg/kg), IPRN (5 mg/kg), a-naphthoflavone (7 mg/kg) (positive control) (Bachmann et al, 1993), or vehicle was dosed intravenously for each group, respectively. The 5 mg/kg dose of PRN and IPRN was selected based on maximum doses in humans (60 mg/d, p.o.)…”

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confidence: 99%

Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies

et al. 2013

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Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC 50 , k inact , and K I values were 10.4 6 1.4 mM, 0.060 6 0.002 min 21 , and 1.13 6 0.12 mM for PRN, and 7.1 6 0.6 mM, 0.10 6 0.01 min 21 , and 1.95 6 0.31 mM for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC 50 values of 0.26 6 0.01 mM and 0.22 6 0.03 mM for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with k inact and K I values of 0.050 6 0.002 min 21 and 0.40 6 0.06 mM, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71-and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24-and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug-drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN.

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“…To determine whether PCB 104-mediated activation of CYP1A1 and PARP mediates the observed endothelial cell dysfunction we pharmacologically inhibited CYP1A1 with α-naphthoflavone [28] and PARP with PJ-34 [29]. …”

Section: Resultsmentioning

confidence: 99%

PCB-induced endothelial cell dysfunction: Role of poly(ADP-ribose) polymerase

Helyar¹,

Patel²,

Headington³

et al. 2009

Biochemical Pharmacology

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Polychlorinated biphenyls (PCBs) are persistent environmental pollutants implicated in the development of pro-inflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. PCB exposure of endothelial cells results in increased cellular oxidative stress, activation of stress and inflammatory pathways leading to increased expression of cytokines and adhesion molecules and ultimately cell death, all of which can lead to development of atherosclerosis. To date no studies have been performed to examine the direct effects of PCB exposure on the vasculature relaxant response which if impaired may predispose individuals to hypertension, an additional risk factor for atherosclerosis. Overactivation of the DNA repair enzyme poly(ADPribose) polymerase (PARP) following oxidative/nitrosative stress in endothelial cells and subsequent depletion of NADPH has been identified as a central mediator of cellular dysfunction. The aim therefore was to investigate whether 2,2′,4,6,6′-pentachlorobiphenyl (PCB 104) directly causes endothelial cell dysfunction via increased oxidative stress and subsequent overactivation of PARP. Exposure of ex vivo rat aortic rings to PCB 104 impaired the acetylcholine-mediated relaxant response, an effect that was dependent on both concentration and exposure time. In vitro exposure of mouse endothelial cells to PCB 104 resulted in increased cellular oxidative stress through activation of the cytochrome p450 enzyme CYP1A1 with subsequent overactivation of PARP and NADPH depletion. Pharmacological inhibition of CYP1A1 or PARP protected against the PCB 104-mediated endothelial cell dysfunction. In conclusion, the environmental contaminants, PCBs, can activate PARP directly impairing endothelial cell function that may predispose exposed individuals to development of hypertension and cardiovascular disease.

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In vivo Evidence that Theophylline Is Metabolized Principally by CYP1A in Rats

Cited by 15 publications

References 17 publications

The Influence of Anesthetic Agents on Rat Hepatic Cytochromes P450 in vivo

The Influence of Anesthetic Agents on Rat Hepatic Cytochromes P450 in vivo

Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies

PCB-induced endothelial cell dysfunction: Role of poly(ADP-ribose) polymerase

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