Metabolite complex formation of orphenadrine with cytochrome P450

Roos, Peter H.; Mahnke, Axel

doi:10.1016/0006-2952(96)00140-2

Cited by 9 publications

(15 citation statements)

References 42 publications

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“…ORP is reported to inhibit P450 2B 1 by formation of a metabolic intermediate complex (Reidy et al, 1989); such a complex may also be formed in vivo, but could dissociate during the isolation of liver microsomes. Moreover, the time course for the effects of ORP on liver P450 may be crucial, given the difficulty in detecting an inhibitory complex in isolated liver microsomes either 14 h (Reidy et al, 1989) or 2-8 h (as in our study) after ORP injection (also see Roos and Mahnke, 1996). This could explain the lack of effect of PB20+ORP on the net extent of IF N-dechloroethylation in the present study.…”

Section: Discussionmentioning

confidence: 57%

“…Although ORP addition in vitro to liver microsomes prepared from rats pretreated with the PB20 induction schedule did restore a certain level of androstenedione 16[-hydroxylase inhibition, this inhibitory effect should be cautiously interpreted, given that significant inhibition was also observed, albeit to a lesser extent, for CYP3A-dependent androstenedione 6,B-hydroxylase activity. Indeed, ORP might lack complete P450-form specificity as other investigators have recently reported ORP inhibition of P450 3A activities (Roos and Mahnke, 1996;Royer et al, 1996).…”

Section: Discussionmentioning

confidence: 97%

“…The inhibition of P450 2B 1 by MTP results from its ability to serve as a non-covalent ligand for the P450 haem prosthetic group, precluding investigations of its in vivo inhibitory effects using liver microsomes isolated from MTP-treated rats. In contrast, the anti-Parkinson drug ORP, reported to be striking inhibitory toward P450 2B 1-dependent androstenedione 16p-hydroxylase activity in vitro using PB-induced rat liver microsomes (Reidy et al, 1989) and also inhibitory to P450 2C1 1 in in vivo experiments using uninduced adult male rats (Roos and Mahnke, 1996), proved to be inefficient in vivo for limiting the fraction of IF undergoing Ndechloroethylation. Inhibition by ORP was observed when this P450 inhibitor was added to liver microsomes in vitro but was not observed in liver microsomes isolated from PB-induced rats given ORP either 2 or 8 h before killing.…”

Section: Discussionmentioning

confidence: 99%

“…The macrolide antibiotic triacetyloleandomycin (TAO) forms covalent metabolic intermediate complexes by interaction with the active centres of P450 3A enzymes (Pessayre et al, 1981;Chang et al, 1994;Ono et al, 1996), whereas the anti-Parkinson agent orphenadrine (ORP) forms analogous complexes with several liver P450s, including P450 2Cll and P450 2B1 (Reidy et al, 1989;Roos and Mahnke, 1996). This complexation, in turn, results in an inhibition of these P450s.…”

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confidence: 99%

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Modulation of P450-dependent ifosfamide pharmacokinetics: a better understanding of drug activation in vivo

Brain

Yu²,

Gustafsson³

et al. 1998

Br J Cancer

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Summary The anti-cancer prodrug ifosfamide (IF) is metabolized by liver P450 enzymes by two alternative pathways. IF is activated to 4-hydroxy IF (4-OH-IF), which ultimately yields the alkylating mustard isophosphoramide, whereas IF N-dechlororethylation inactivates the drug and produces the neurotoxic metabolite chloroacetaldehyde (CA). Both reactions are catalysed by multiple liver P450 enzymes in vitro in isolated rat liver microsomes. The present pharmacokinetic study investigates the potential for modulation of these alternative pathways of IF metabolism in vivo using the adult male Fischer 344 rat model. Rats were treated with IF alone or in conjunction with various P450 inducers and inhibitors in an effort to improve the balance between drug activation and drug inactivation. Plasma concentrations, areas under the curve (AUC) and half-lives were calculated for 4-OH-IF and CA, allowing estimations of the extent of IF activation and deactivation/toxification. Induction of liver P450 2B enzymes by 4-day high-dose phenobarbital (PB) pretreatment significantly decreased the fraction of IF undergoing 4-hydroxylation (AUC4 OH -1 AUC4-OH IF+AUCCA), from 37% to 22% of total metabolism (P < 0.05), consistent with in vitro findings that the PBinducible P450 enzyme 2B1 plays a major role in IF N-dechloroethylation. Pretreatment with the P450 3A inducer dexamethasone proportionally decreased the AUC for both IF metabolites, without any net impact on the fraction of IF undergoing metabolic activation. By contrast, the P450 2B1 inhibitor metyrapone preferentially increased the AUC for the 4-hydroxylation pathway in 3-day low-dose PB-induced rats, thereby increasing the total fraction of IF metabolized via the activation pathway from 36% to 54% (P < 0.05), whereas the P450 inhibitors orphenadrine and troleandomycin had no significant affect on AUC values. These findings demonstrate specific roles for P450 2B and 3A enzymes in catalysing these pathways of IF metabolism in vivo, and demonstrate the potential for modulation of IF's alternative metabolic pathways in a therapeutically useful manner. These studies also highlight several clinically relevant drug interactions that may occur during concomitant administration of IF with drugs and other compounds that modulate hepatic P450 enzyme levels.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Modulation of P450-dependent ifosfamide pharmacokinetics: a better understanding of drug activation in vivo

Brain

Yu²,

Gustafsson³

et al. 1998

Br J Cancer

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“…387 The inducer-dependent modulations of the CYP isoenzyme profile detected by LA-ICP-SFMS were in accordance with published data on expression and inducibility of CYP enzymes obtained by other analytical methods. 388 To trace the biological fate of a peptide that is devoid of suitable heteroelements, Kretschy et al used an indium-containing DOTA complex for tagging. 389 They relied on ICP-SFMS to show that the tagged peptide was taken up by human umbilical-cord epithelial cells.…”

Section: Element-specific Detection Of Small Molecules In Biological mentioning

confidence: 99%

Inductively Coupled Plasma Mass Spectrometry

Jakubowski

Horsky

Roos

et al. 2014

Sector Field Mass Spectrometry for Elemental and Isotopic Analysis

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ICP-MS is based on the formation of (preferentially monovalent positively) charged atomic ions in an inductively coupled Ar plasma at almost 10 000 K. The ions formed are transferred from the plasma source at ambient pressure into a mass separator operated at high vacuum via a set of cones. The ions are separated according to their mass/charge ratio in the mass separator (quadrupole, magnetic sector field or time-of-flight mass separator). In most cases, the ions are detected using a secondary electron multiplier; in some set-ups (also) a Faraday cup can be used. Single-collector (scanning mass spectrometer usually used for quantitative elemental analysis) or multicollector (static operation of mass spectrometer for precise isotope ratio analysis) configurations can be found (Figures 12.1 and 12.2).

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Upregulation of cytochromes P450 2B in rat liver by orphenadrine

Murray

Fiala-Beer

Sutton

2003

British J Pharmacology

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1 The alkylamine drug orphenadrine (ORPH) is an inducer and inhibitor of the microsomal cytochrome P450 (CYP) system in mammals. This study evaluated the selectivity of CYP induction by ORPH in rat liver. 2 Immunoblot analysis indicated that ORPH was a selective inducer of the phenobarbitone (PB)-inducible CYP2B in rat liver. CYP2B protein was increased to B14-fold of levels in untreated rat liver. By comparison PB increased CYP2B expression 40-fold. Corresponding increases in the activity of CYP2B-dependent androstenedione 16b-hydroxylation were measured in microsomes from ORPH and PB-induced rats. 3 Northern analysis indicated that CYP2B1/2 mRNA was increased in ORPH-induced rat liver. Consistent with this finding, ORPH was found to activate a PB-responsive enhancer module in constitutive androstane receptor (CAR)-transfected Hep G2 cells. 4 Other alkylamines like troleandomycin impair CYP turnover. We tested whether ORPH induction of CYP2B may include a post-translational component. In PB-pretreated animals ORPH administration delayed the loss of CYP2B after PB withdrawal, but no evidence for altered turnover was found. 5 These studies establish ORPH as a selective inducer of CYP2B in rat liver. Induction appears to be mediated pretranslationally by CAR activation of CYP2B gene transcription. Post-translational stabilisation by an ORPH metabolite does not elicit induction. Induction of CYP2B may influence pharmacokinetic interactions involving ORPH.

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Metabolite complex formation of orphenadrine with cytochrome P450

Cited by 9 publications

References 42 publications

Modulation of P450-dependent ifosfamide pharmacokinetics: a better understanding of drug activation in vivo

Modulation of P450-dependent ifosfamide pharmacokinetics: a better understanding of drug activation in vivo

Inductively Coupled Plasma Mass Spectrometry

Upregulation of cytochromes P450 2B in rat liver by orphenadrine

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