Identification of Human Cytochrome P450 Isozymes Involved in Diphenhydramine <i>N</i>-Demethylation

Akutsu, Tomoko; Kobayashi, Kaoru; Sakurada, Koichi; Ikegaya, Hiroshi; Furihata, Tomomi; Chiba, Kazuhiro

doi:10.1124/dmd.106.012088

Cited by 61 publications

(23 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[ 504,505]. These metabolic pathways are thought to be major pathways in humans CYP1A2, 2C9, and 2C19 are low-affinity catalysing components for the N-demethylation of diphenhydramine, a member of the ethanolamine class of first-generation antihistamine agents, while CYP2D6 catalyzes this reaction as the high-affinity enzyme [506]. In addition, CYP2C18 and 2B6 also play a role at relatively higher substrate concentration (20 M) [507].…”

Section: Diphenhydraminementioning

confidence: 98%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

View full text Add to dashboard Cite

Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

show abstract

Section: Diphenhydraminementioning

confidence: 98%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

View full text Add to dashboard Cite

show abstract

“…Diphenhydramine undergoes hepatic metabolism by cytochrome P (CYP) 2d6, 35 and poor metabolism by CYP2d6 polymorphism is more common in white than Japanese. 36 On the other hand, bepotastine undergoes negligible hepatic metabolism and is less likely to be influenced by genetic variation.…”

Section: Discussionmentioning

confidence: 99%

Next-Day Residual Sedative Effect After Nighttime Administration of an Over-the-Counter Antihistamine Sleep Aid, Diphenhydramine, Measured by Positron Emission Tomography

Zhang¹,

Tashiro²,

Shibuya³

et al. 2010

Journal of Clinical Psychopharmacology

View full text Add to dashboard Cite

Antihistamines often are self-administered at night as over-the-counter (OTC) sleep aids, but their next-day residual sedative effect has never been evaluated using a reliable quantitative method such as positron emission tomography (PET). We performed a double-blind, placebo-controlled, crossover study in which we evaluated the residual effect the next day after nighttime administration of diphenhydramine, a commonly used OTC sleep aid, in terms of brain H₁ receptor occupancy (H₁RO) measured using ¹¹C-doxepin-PET. We also compared the results of diphenhydramine with those of bepotastine, a second-generation antihistamine. Eight healthy adult male subjects underwent PET measurement the morning (11:00) after random oral administration of diphenhydramine (50 mg), bepotastine (10 mg), or placebo the night before (23:00). Binding potential ratios and H₁ROs were calculated in different brain regions of interest such as the cingulate gyrus, frontotemporal cortex, and cerebellum. Subjective sleepiness and plasma drug concentration also were measured. Calculation of binding potential ratios revealed significantly lower values for diphenhydramine than for bepotastine or placebo in all regions of interest (P < 0.01). Cortical mean H₁RO after diphenhydramine treatment was 44.7% compared with 16.6% for bepotastine treatment (P < 0.01). Subjective sleepiness was not significantly different among the subjects treated with each test drug or the placebo. In conclusion, the next-day residual sedative effect after nighttime administration of the OTC sleep aid diphenhydramine was verified for the first time by direct PET measurement of H₁RO. Taking into account the possible hangover effect of OTC antihistamine sleep aids, care needs to be taken during their administration.

show abstract

“…In addition to these, CYP-activity phenotyped liver preparations are used to reflect the formation of the metabolites, so that metabolite formation correlating with certain CYP isoform activity in the livers suggests high involvement of that particular CYP isoform. A large number of studies for identification of the CYP enzyme responsible for metabolism of some particular compound are reported and some of the most recent ones are cited here [93][94][95][96][97]. Similarly, articles describing the role of analytical techniques in the identification of UDP-glucuronosyltransferase enzyme isoforms responsible for glucuronide conjugation have been published [98][99][100].…”

Section: Hepatic Metabolism Studiesmentioning

confidence: 96%

From Known Knowns to Known Unknowns: Predicting in Vivo Drug Metabolites

Pelkonen

Tolonen²,

Korjamo³

et al. 2009

Bioanalysis

View full text Add to dashboard Cite

'It is better to be useful than perfect'. This review attempts to critically cover and assess the currently available approaches and tools to answer the crucial question: Is it possible (and if it is, to what extent is it possible) to predict in vivo metabolites and their abundances on the basis of in vitro and preclinical animal studies? In preclinical drug development, it is possible to produce metabolite patterns from a candidate drug by virtual means (i.e., in silico models), but these are not yet validated. However, they may be useful to cover the potential range of metabolites. In vitro metabolite patterns and apparent relative abundances are produced by various in vitro systems employing tissue preparations (mainly liver) and in most cases using liquid chromatography-mass spectrometry analytical techniques for tentative identification. The pattern of the metabolites produced depends on the enzyme source; the most comprehensive source of drug-metabolizing enzymes is cultured human hepatocytes, followed by liver homogenate fortified with appropriate cofactors. For specific purposes, such as the identification of metabolizing enzyme(s), recombinant enzymes can be used. Metabolite data from animal in vitro and in vivo experiments, despite known species differences, may help pinpoint metabolites that are not apparently produced in in vitro human systems, or suggest alternative experimental approaches. The range of metabolites detected provides clues regarding the enzymes attacking the molecule under study. We also discuss established approaches to identify the major enzymes. The last question, regarding reliability and robustness of metabolite extrapolations from in vitro to in vivo, both qualitatively and quantitatively, cannot be easily answered. There are a number of examples in the literature suggesting that extrapolations are generally useful, but there are only a few systematic and comprehensive studies to validate in vitro-in vivo extrapolations. In conclusion, extrapolation from preclinical metabolite data to the in vivo situation is certainly useful, but it is not known to what extent.

show abstract

Identification of Human Cytochrome P450 Isozymes Involved in Diphenhydramine N-Demethylation

Cited by 61 publications

References 26 publications

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Next-Day Residual Sedative Effect After Nighttime Administration of an Over-the-Counter Antihistamine Sleep Aid, Diphenhydramine, Measured by Positron Emission Tomography

From Known Knowns to Known Unknowns: Predicting in Vivo Drug Metabolites

Contact Info

Product

Resources

About