Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron.

Bloomer, J. C.; Baldwin, SJ; Smith, G. M.; Ayrton, A.; Clarke, S. E.; Chenery, R J

doi:10.1111/j.1365-2125.1994.tb04397.x

Cited by 82 publications

(51 citation statements)

References 27 publications

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“…In order to assess the role of CYP2C9 and CYP3A4 in celecoxib hydroxylation, samples were pretreated with either sulphaphenazole (SPZ, 10 µM; [18,19]) or triacetyloleandomycin (TAO, 50 µM; [20]). TAO and SPZ were both dissolved in methanol, which was evaporated to dryness before addition of the incubation mixture.…”

Section: Celecoxib Metabolismmentioning

confidence: 99%

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Sandberg

Yaşar

Strömberg

et al. 2002

Brit J Clinical Pharma

102

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Aims Celecoxib is a novel selective cyclooxygenase-2 inhibitor, which is subject to extensive hepatic metabolism. The aims of the present in vitro investigation were 1) to compare the rate of celecoxib hydroxylation by different genetic variants of cytochrome P450 2C9 (CYP2C9), and 2) to identify the enzyme(s) involved in the formation of the major metabolite carboxycelecoxib. Methods Hydroxycelecoxib formation was studied in human liver microsomes from 35 genotyped livers, as well as in yeast microsomes with recombinant expression of different P450 variants. Carboxycelecoxib formation was studied in liver microsomes incubated in the absence or presence of liver cytosol. The metabolites were identified and quantified by h.p.l.c. In addition, hydroxycelecoxib oxidation by different variants of recombinant human alcohol dehydrogenase (ADH1-3) was analysed by spectrophotometric monitoring of NADH generation from NAD + . Results The intrinsic clearance of celecoxib hydroxylation was significantly lower for yeast-expressed CYP2C9.3 (0.14 ml min − 1 nmol − 1 enzyme) compared with CYP2C9.1 (0.44 ml min − 1 nmol − 1 enzyme). In human liver microsomes, a significant 2-fold decrease in the rate of hydroxycelecoxib formation was evident in CYP2C9 * 1/ * 3 samples compared with CYP2C9 * 1/ * 1 samples. There was also a marked reduction (up to 5.3 times) of hydroxycelecoxib formation in a liver sample genotyped as CYP2C9 * 3/ * 3 . However, the CYP2C9 * 2 samples did not differ significantly from CYP2C9 * 1 in any of the systems studied. Inhibition experiments with sulphaphenazole (SPZ) or triacetyloleandomycin indicated that celecoxib hydroxylation in human liver microsomes was mainly dependent on CYP2C9 and not CYP3A4. The further oxidation of hydroxycelecoxib to carboxycelecoxib was completely dependent on liver cytosol and NAD + . Additional experiments showed that ADH1 and ADH2 catalysed this reaction in vitro with apparent K m values of 42 µ M and 10 µ M , respectively, whereas ADH3 showed no activity. Conclusions The results confirm that CYP2C9 is the major enzyme for celecoxib hydroxylation in vitro and further indicate that the CYP2C9 * 3 allelic variant is associated with markedly slower metabolism. Furthermore, it was shown for the first time that carboxycelecoxib formation is dependent on cytosolic alcohol dehydrogenase, presumably ADH1 and/or ADH2.

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Section: Celecoxib Metabolismmentioning

confidence: 99%

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Sandberg

Yaşar

Strömberg

et al. 2002

Brit J Clinical Pharma

102

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“…Tropisetron is metabolized almost entirely by the CYP2D6 isozyme; ondansetron, dolasetron, and palonosetron are metabolized by other CYP isozymes in addition to CYP2D6. Granisetron is the only 5-HT 3 -receptor antagonist that does not involve CYP2D6 in its metabolism and is instead metabolized by members of the CYP3A subfamily [65].…”

Section: -Ht 3 -Receptor Antagonistsmentioning

confidence: 99%

Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications

et al. 2006

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After completing this course, the reader will be able to:1. List the four different genotypes for CYP2D6 polymorphism.2. Understand the potential effects of CYP2D6 polymorphism on the efficacy and safety for drugs metabolized via this enzyme.3. List the ethnic groups that are most frequently affected by genetic variation of the CYP2D6 enzyme. Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com CME CME This material is protected by U.S.

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“…Ondansetron is primarily metabolised by cytochrome 450 enzymes, including CYP 2D6, for which genetic polymorphisms have been identified (Fischer et al, 1994;Dixon et al, 1995;Received 24 December 2002;accepted 24 April 2003Davis et al, 2001Wilkinson 2001). Such enzyme polymorphisms appear not to account for granisetron, which is primarily metabolised by CYP 3 A (Bloomer et al, 1994). Suboptimal levels of ondansetron due to extensive or ultrarapid CYP 2D6 metabolism in patients may not have a detectable impact in phase III trials in unselected patients.…”

Section: Crossover Between 5ht 3 Antagonists In Acute Emesis Failurementioning

confidence: 99%

Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics

Wit

2003

Br J Cancer

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The advent of the 5HT 3 receptor antagonists (5HT 3 antagonists) in the 1990 s and the combination with dexamethasone has resulted in acute emesis protection in 70% of patients receiving highly emetogenic chemotherapy. Despite complete protection in the acute phase, however, 40% of patients as yet have symptoms in the delayed phase. 5HT 3 antagonists and dexamethasone are only modestly effective in this delayed phase. Moreover, the antiemetic protection over repeated cycles is not sustained. Neurokinine 1 receptor antagonists (NK 1 antagonists) belong to a new class of antiemetic agents that specifically target the NK 1 receptor, which is involved in both the acute and, particularly, the delayed phase of emesis. Clinical studies have demonstrated that the addition of NK 1 antagonists to dual therapy with a 5HT 3 antagonist plus dexamethasone improves the acute emesis protection by a further 10 -15%. In the delayed phase, the proportion of patients remaining free of emesis increases by even 20 -30%. Since the effectiveness of this triplet combination was found to be sustained over six cycles of chemotherapy, the chance for an individual patient to remain completely protected during both the acute and the delayed phase over six chemotherapy cycles is nearly doubled. Keywords: Antiemetics; 5HT 3 antagonists; NK 1 antagonists; neurokinine receptor antagonists; substance P Nausea and vomiting are considered as two of the most distressing side effects of anticancer chemotherapy. Chemotherapy-induced emesis has a serious impact on a patient's quality of life and the possibility to complete the planned chemotherapy successfully. Cisplatin is most commonly associated with profound nausea and vomiting, which follows a distinct pattern of an acute phase (0 -24 h after the start of chemotherapy) and a delayed phase that is mostly defined as occurring on days 2 -5 after the chemotherapy. Since severe emesis occurs in virtually all patients who receive a cisplatin dose of X50 mg m À2 , cisplatin-induced nausea and vomiting has served as the model to test anti-emetic agents for highly emetogenic chemotherapy Gralla et al, 1999). CURRENT ROLE OF 5HT 3 ANTAGONISTS PLUS DEXAMETHASONE; ACUTE PHASEBefore the advent of the 5HT 3 antagonists, nausea and vomiting were ranked as the two most distressing side effects of systemic chemotherapy (Coates et al, 1983). The use of 5HT 3 antagonists (ondansetron, granisetron and tropisetron) has provided complete acute emesis protection in 50-70% of patients receiving a first cycle of cisplatin-based chemotherapy . The addition of dexamethasone to 5HT 3 antagonists has improved the complete protection rate by a further 10 -15%, resulting in a total complete acute emesis protection in 65 -80% of patients .

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Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron.

Cited by 82 publications

References 27 publications

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications

Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics

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