CYP1A1 Is a Major Enzyme Responsible for the Metabolism of Granisetron in Human Liver Microsomes

Nakamura, Hirokun; Ariyoshi, Noritaka; Okada, Keiko; Nakasa, Hiromitsu; Nakazawa, Katsuhito; Kitada, Munehiro

doi:10.2174/138920005774330666

Cited by 37 publications

(28 citation statements)

References 16 publications

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“…Since many tissues exhibit esterase activity it is not surprising that predicted CL from hepatic metabolism underestimates total CL (predicted CL 6 vs observed Cl 18.8 ml/min/kg). Similarly granisetron is reported to be primarily metabolised by the extra hepatic CYP1A1 [29]. These examples exemplify the importance of a priori elucidation of metabolite routes and reaction phenotyping for candidate drugs.…”

Section: Prediction Of Pk Parameters Clearancementioning

confidence: 92%

Evaluation of Human Pharmacokinetics, Therapeutic Dose and Exposure Predictions Using Marketed Oral Drugs

McGinnity¹,

Collington²,

Austin³

et al. 2007

CDM

111

127

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In this article approaches to predict human pharmacokinetics (PK) are discussed and the capability of the exemplified methodologies to estimate individual PK parameters and therapeutic dose for a set of marketed oral drugs has been assessed. For a set of 63 drugs where the minimum efficacious concentration (MEC) and human PK were known, the clinical dose was shown to be well predicted or in some cases over-estimated using a simple one-compartment oral PK model. For a subset of these drugs, in vitro potency against the primary human targets was gathered, and compared to the observed MEC. When corrected for plasma protein binding, the MEC of the majority of compounds was < or=3 fold over the respective in vitro target potency value. A series of in vitro and in vivo experiments were conducted to predict the human PK parameters. Metabolic clearance was generally predicted well from human hepatocytes. Interestingly, for this compound set, allometry or glomerular filtration rate (GFR) ratio methods appeared to be applicable for renal CL even where CL(renal) > GFR. For approximately 90% of compounds studied, the predicted CL using in vitro-in vivo (IVIV) extrapolation together with a CL(renal) estimate, where appropriate, was within 2-fold of that observed clinically. Encouragingly volume of distribution at steady state (V(ss)) estimated in preclinical species (rat and dog) when corrected for plasma protein binding, predicted human V(ss) successfully on the majority of occasions--73% of compounds within 2-fold. In this laboratory, absorption estimated from oral rat PK studies was lower than the observed human absorption for most drugs, even when solubility and permeability appeared not to be limiting. Preliminary data indicate absorption in the dog may be more representative of human for compounds absorbed via the transcellular pathway. Using predicted PK and MEC values estimated from in vitro potency assays there was a good correlation between predicted and observed dose. This analysis suggests that for oral therapies, human PK parameters and clinical dose can be estimated from a consideration of data obtained from in vitro screens using human derived material and in vivo animal studies. The benefits and limitations of this holistic approach to PK and dose prediction within the drug discovery process are exemplified and discussed.

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Section: Prediction Of Pk Parameters Clearancementioning

confidence: 92%

Evaluation of Human Pharmacokinetics, Therapeutic Dose and Exposure Predictions Using Marketed Oral Drugs

McGinnity¹,

Collington²,

Austin³

et al. 2007

CDM

111

127

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Section: Discussionmentioning

confidence: 99%

“…20,21) It has been previously reported that granisetron 7-hydroxylation, a major metabolic pathway, is almost exclusively catalyzed by CYP1A1 in human liver microsomes. 20) The potent inhibition of CYP1A1 by CBD might influence the pharmacokinetics of granisetron. At present, however, the roles of CYP1A1 and CBD-mediated inhibition in drug clearance are limited because of a limited number of drugs metabolized by CYP1A1 and very low constitutive expression of CYP1A1 in the liver.…”

Section: Discussionmentioning

confidence: 99%

“…17,18) CYP1A1 is important in the bioactivation of procarcinogens, such as polycyclic aromatic hydrocarbons and heterocyclic amines. 16,19) Furthermore, this enzyme plays a role in the metabolism of several drugs including granisetron 20) and dacarbazine. 21) Therefore, potent inhibition of CYP1A1 by CBD may not only lead to the suppression of metabolic activation of procarcinogens but also influence the pharmacokinetics of drugs metabolized mainly by CYP1A1.…”

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confidence: 99%

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Structural Requirements for Potent Direct Inhibition of Human Cytochrome P450 1A1 by Cannabidiol: Role of Pentylresorcinol Moiety

Yamaori

Okushima

Masuda

et al. 2013

Biological & Pharmaceutical Bulletin

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Our recent work has shown that cannabidiol (CBD) exhibits the most potent direct inhibition of human cytochrome P450 1A1 (CYP1A1) among the CYP enzymes examined. However, the mechanism underlying this CBD inhibition remains to be clarified. Thus, to elucidate the structural requirements for the potent inhibition by CBD, the effects of CBD and its structurally related compounds on CYP1A1 activity were investigated with recombinant human CYP1A1. Olivetol, which corresponds to the pentylresorcinol moiety of CBD, inhibited the 7-ethoxyresorufin O-deethylase activity of CYP1A1; its inhibitory effect (IC 50 =13.8 µm)was less potent than that of CBD (IC 50 =0.355 µm). In contrast, d-limonene, which corresponds to the terpene moiety of CBD, only slightly inhibited CYP1A1 activity. CBD-2′-monomethyl ether (CBDM) and CBD-2′,6′-dimethyl ether inhibited CYP1A1 activity with IC 50 values of 4.07 and 23.0 µm, respectively, indicating that their inhibitory effects attenuated depending on the level of methylation on the free phenolic hydroxyl groups in the pentylresorcinol moiety of CBD. Cannabidivarin inhibited CYP1A1 activity, although its inhibitory potency (IC 50 =1.85 µm) was lower than that of CBD. The inhibitory effects of Δ 9 -tetrahydrocannabinol and cannabielsoin (IC 50 s ≈10 µm), which contain a free phenolic hydroxyl group and are structurally constrained, were less potent than that of CBDM, which contains a free phenolic hydroxyl group and is rotatable between pentylresorcinol and terpene moieties. These results suggest that the pentylresorcinol structure in CBD may have structurally important roles in direct CYP1A1 inhibition, although the whole structure of CBD is required for overall inhibition.Key words cannabidiol; cytochrome P450 1A1; direct inhibition; structural requirement; pentylresorcinol Cannabidiol (CBD), one of the major constituents in marijuana, 1) is not psychoactive but has several pharmacological effects such as prolonging drug-induced sleep, antiepileptic, anxiolytic, and antiemetic actions.2) CBD is also known to inhibit hepatic microsomal drug metabolism in mammals. [3][4][5] A previous clinical study has shown that the administration of CBD reduces the systemic clearance of hexobarbital, which is metabolized by cytochrome P450 2C9 (CYP2C9), in human subjects.6) In vitro studies by Jaeger et al. 7) and us 8-13) demonstrated that CBD inhibits catalytic activities of CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in human liver microsomes and/or recombinant CYP enzymes. Interestingly, we have recently reported that the CBD-mediated direct inhibition of human CYP1A1 activity is the strongest among those of CYP activities reported so far.8) In addition, CYP1A1 was more potently inhibited by CBD than by the other major phytocannabinoids examined. 8) CYP1A1 is expressed in various tissues including the liver and lung, [14][15][16] although the constitutive expression level is very low. In general, hepatic and pulmonary CYP1A1 is induced by exposure to tobacco smoke. 17,18) C...

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“…CYP1A1-mediated N-hydroxylation and O-dealkylation of riluzole proceeds at a lower K m and a higher biotransformation rate than the hepatic metabolism of this compound by CYP1A2 [180]. CYP1A1 also plays a role in the metabolism of another neuroactive drug, granisetron [181]. Granisetron, a serotonin 5-HT3 receptor antagonist used to treat chemotherapyinduced nausea and vomiting, is metabolized primarily by CYP1A1 to 7-hydroxygranisetron and to a lesser degree to 9′-desmethylgranisetron by CYP1A1 and CYP3A4.…”

Section: Vitamin a [219] Nutrientmentioning

confidence: 99%

Regulation of CYP1A1 by heavy metals and consequences for drug metabolism

Anwar-Mohamed

Elbekai

El‐Kadi

2009

Expert Opinion on Drug Metabolism & Toxicology

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Cytochrome P450 1A1 (CYP1A1) is a hepatic and extrahepatic enzyme that is regulated by the aryl hydrocarbon receptor signaling pathway. With the growing human exposure to heavy metals, emerging evidence suggests that heavy metals exposure alter CYP1A1 enzyme activity. Heavy metals regulate CYP1A1 at different levels of its aryl hydrocarbon receptor signaling pathway in a metal-and species-dependent manner. The importance of CYP1A1 emerges from the fact that it has been always associated with the metabolism of pro-carcinogenic compounds to highly carcinogenic metabolites. However, recently CYP1A1 has gained status along with other cytochrome P450 enzymes in the metabolism of drugs and mediating drug-drug interactions. In addition, CYP1A1 has become a therapeutic tool for the bioactivation of prodrugs, particularly cytotoxic agents. In this review, we shed light on the effect of seven heavy metals, namely arsenic, mercury, lead, cadmium, chromium, copper and vanadium, on CYP1A1 and the consequences on drug metabolism.

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CYP1A1 Is a Major Enzyme Responsible for the Metabolism of Granisetron in Human Liver Microsomes

Cited by 37 publications

References 16 publications

Evaluation of Human Pharmacokinetics, Therapeutic Dose and Exposure Predictions Using Marketed Oral Drugs

Evaluation of Human Pharmacokinetics, Therapeutic Dose and Exposure Predictions Using Marketed Oral Drugs

Structural Requirements for Potent Direct Inhibition of Human Cytochrome P450 1A1 by Cannabidiol: Role of Pentylresorcinol Moiety

Regulation of CYP1A1 by heavy metals and consequences for drug metabolism

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