Oxidative dehalogenation of 2-fluoro-17α-ethynyloestradiol in vivo

Morgan, Paul; Maggs, James L.; Page, Philip C. Bulman; Park, B.K.

doi:10.1016/0006-2952(92)90064-p

Cited by 16 publications

(5 citation statements)

References 40 publications

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“…For example, for the structures of M4 and M9, a hydroxyl group was proposed to replace the chlorine on the 3-chlorophenylpiperazine moiety via oxidative dehalogenation biotransformation. 25,26 Quick reference of the EMS data confirmed these assignments, as both metabolites (M4 at 20.2 min, M9 at 22.9 min) lost the characteristic chlorine isotope pattern. A total of 22 metabolites (Fig.…”

Section: Resultssupporting

confidence: 74%

‘N‐in‐one’ strategy for metabolite identification using a liquid chromatography/hybrid triple quadrupole linear ion trap instrument using multiple dependent product ion scans triggered with full mass scan

Gohdes

Shou

2007

Rapid Comm Mass Spectrometry

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This paper describes a new strategy that utilizes the fast trap mode scan of the hybrid triple quadrupole linear ion trap (QqQ(LIT)) for the identification of drug metabolites. The strategy uses information-dependent acquisition (IDA) where the enhanced mass scan (EMS), the trap mode full scan, was used as the survey scan to trigger multiple dependent enhanced product ion scans (EPI), the trap mode product ion scans. The single data file collected with this approach not only includes full scan data (the survey), but also product ion spectra rich in structural information. By extracting characteristic product ions from the dependent EPI chromatograms, we can provide nearly complete information for in vitro metabolites that otherwise would have to be obtained by multiple precursor ion scan (prec) and constant neutral loss (NL) analysis. This approach effectively overcomes the disadvantages of traditional prec and NL scans, namely the slow quadrupole scan speed, and possible mass shift. Using nefazodone (NEF) as the model compound, we demonstrated the effectiveness of this strategy by identifying 22 phase I metabolites in a single liquid chromatography/tandem mass spectrometry (LC/MS/MS) run. In addition to the metabolites reported previously in the literature, seven new metabolites were identified and their chemical structures are proposed. The oxidative dechlorination biotransformation was also discovered which was not reported in previous literature for NEF. The strategy was further evaluated and worked well for the fast discovery setting when a ballistic gradient elution was used, as well as for a simulated in vivo setting when the incubated sample (phase I metabolites) was spiked to control human plasma extract and control human urine.

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Section: Resultssupporting

confidence: 74%

‘N‐in‐one’ strategy for metabolite identification using a liquid chromatography/hybrid triple quadrupole linear ion trap instrument using multiple dependent product ion scans triggered with full mass scan

Gohdes

Shou

2007

Rapid Comm Mass Spectrometry

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“…In a simple saturated system, the inductive effect of fluorine should reduce the susceptibility of adjacent groups to attack by P450 enzymes. On the contrary the presence of fluorine ortho to a phenolic group might increase its reactivity as a nucleophile in methylation and glucuronidation reactions [35,53,54].…”

Section: Modification Of Metabolically Labile Spotsmentioning

confidence: 97%

Preclinical Pharmacokinetics: An Approach Towards Safer and Efficacious Drugs

Singh

2006

CDM

240

117

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Lack of efficacy and toxicity are considered to be major reasons for drug failures and pharmacokinetics governs them to a large extent. Compound with favorable pharmacokinetics is more likely to be efficacious and safe. Therefore, the preclinical pharmacokinetic evaluation should be comprehensive enough to ensure that compounds do not fail in the clinic. Preclinical ADME screening facilitates early elimination of weak candidates and directs the entire focus of the drug development program towards fewer potential lead candidates. Hence, it is mandatory that the pre-clinical candidates are subjected to as many possible reality checks. Reliance on in-vitro tests should be minimized because they do not represent the real physiological environment but rather slow down the pace of a drug discovery program. Compounds can be straight away subjected to in-vivo high throughput screens such as cassette dosing, cassette analysis or rapid rat screen etc. Candidates with the desired in-vivo pharmacokinetic profile may be further profiled in-vitro, using assays such as metabolic stability, reaction phenotyping, CYP-450 inhibition and induction, plasma protein binding etc. in human microsomes, human recombinant CYP-450 enzymes and human plasma. This also provides an early indication of whether the compound which worked in animals would work in human as well. In-vitro metabolic stability profile is a qualitative as well as quantitative comparison of metabolism of a compound in human and animal models. It helps in identifying the right model for toxicity studies. Extensive metabolism is generally considered a liability as it limits the systemic exposure and shortens the half-life of a compound. Several strategies such as reduction of lipophilicity, modification and / or blocking of metabolically soft spots and use of enzyme inhibitors; have been developed to combat metabolism. In spite of several concerns, the fact that active metabolites of several marketed drugs have been developed as drugs with better efficacy, safety and pharmacokinetics profile; cannot be denied. Therefore, instead of considering metabolic instability a liability it can be exploited as a tool for discovering better drugs. It is equally important to identify the metabolic pathways of the drug candidates by conducting in-vitro CYP450 reaction phenotyping assays. The identification of drug metabolizing enzymes involved in the major metabolic pathways of a compound helps in predicting the probable drug-drug interactions in human. Compounds with more than one metabolic pathway have less likelihood of clinically significant drug interactions. In-vitro CYP450 inhibition and induction screens are used to evaluate the potential of compound towards drug - drug interactions and the most prone candidates may either be discarded or taken ahead with a caution. It is known that only unbound drug is pharmacologically active and therefore the assessment of bound fraction by the estimation of plasma protein binding of a compound is another important parameter to be explored in...

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“…The ease of halogen elimination in this cytochrome P450 model system (), and also in a microsomal cytochrome P450-catalyzed oxidative dehalogenation (), decreases in the order F > Cl > Br > I, as well as with the introduction of additional electron-withdrawing halogen substituents in the aromatic ring ( , ). This observation has implications in the field of drug and agrochemical development, because incorporation of a fluorine substituent in a drug or agrochemical has been suggested as a means of blocking biodegradation or bioactivation of the compound ( − ).…”

Section: Mechanism Of Benzoquinone Formationmentioning

confidence: 99%