Species differences in metabolism of ketotifen in rat, rabbit and man: Demonstration of similar pathways and in cultured hepatocytes

Bigot, J. F. Le; Bégué, Jean-Marc; Kiechel, J. R.; Guillouzo, André

doi:10.1016/0024-3205(87)90037-3

Cited by 70 publications

(22 citation statements)

References 13 publications

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“…Regarding rat, the in vitro kinetics for glucuronidation at a tertiary amine of a substrate was determined for the first time. The observed minimal formation, at most, of 1a N ϩ -glucuronide for both rat and dog microsomes was consistent with previous studies of various substrates in which the extent of N ϩ -glucuronide formation was much less than in other species, including human (Beckett and Ali, 1978;Hucker et al, 1978;Le Bigot et al, 1987;Magdalou et al, 1992;Li et al, 2001;Soars et al, 2001). For the most part, the UGTs involved in the observed catalyzes in animals are not resolved.…”

Section: Discussionsupporting

confidence: 89%

“…Large interspecies differences were observed between guinea pig, human, and rabbit in K m and V max values for formation of 1a N ϩ -glucuronide, 8-and 12-fold, respectively. However, that there was only 1.5-fold difference observed in the resultant V max /K m ratios lends support to previous use of the guinea pig and rabbit in the study of N-glucuronidation at a tertiary amine (Beckett and Ali, 1978;Lehman et al, 1983;Le Bigot et al, 1987;Coughtrie and Sharp, 1991;Remmel and Sinz, 1991;Magdalou et al, 1992;Styczynski et al, 1992;Bruck et al, 1997;Li et al, 2001). Regarding rat, the in vitro kinetics for glucuronidation at a tertiary amine of a substrate was determined for the first time.…”

Section: Discussionsupporting

confidence: 83%

“…Some studies have indicated that such N-glucuronidation is only significant in primates (Hucker et al, 1978;Fischer et al, 1980). However, evidence has accumulated for guinea pigs and rabbits that N ϩ -glucuronides are formed substantially as urinary (Beckett and Ali, 1978;Le Bigot et al, 1987;Remmel and Sinz, 1991) and hepatic in vitro (Lehman et al, 1983;Coughtrie and Sharp, 1991;Remmel and Sinz, 1991;Magdalou et al, 1992;Styc-zynski et al, 1992;Bruck et al, 1997;Li et al, 2001) metabolites of certain substrates. There are few reports known to the authors about the formation of such metabolites in rats, and all involve metabolism at an aromatic tertiary amine (Bieder et al, 1983;MacRae et al, 1990;Magdalou et al, 1992;Seaton et al, 1993;Singh et al, 2001).…”

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confidence: 99%

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Quaternary Ammonium-Linked Glucuronidation of 1-Substituted Imidazoles by Liver Microsomes: Interspecies Differences and Structure-Metabolism Relationships

Vashishtha¹,

Hawes²,

McCann³

et al. 2002

Drug Metabolism and Disposition

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:N-Glucuronidation at an aromatic tertiary amine of 5-membered polyaza ring systems was investigated for a model series of eight 1-substituted imidazoles in liver microsomes from five species. The major objectives were to investigate substrate specificities of the series in human microsomes and interspecies variation for the prototype molecule, 1-phenylimidazole. The formed quaternary ammonium-linked metabolites were characterized by positive ion electrospray mass spectrometry. The incubation conditions for the N-glucuronidation of 1-substituted imidazoles were optimized; where for membrane disrupting agents, alamethicin was more effective than the detergents examined. The need to optimize alamethicin concentration was indicated by 4-fold interspecies variation in optimal concentration and by a change in effect from removal of glucuronidation latency to inhibition on increasing concentration. For the four species with quantifiable N-glucuronidation of 1-phenylimidazole, there were 8-and 18-fold variations in the determined apparent K m (range, 0.63 to 4.8 mM) and V max (range, 0.08 to 1.4 nmol/min/mg of protein) values, respectively. The apparent clearance values (V max /K m ) were in the following order: human Х guinea pig Х rabbit > rat Х dog (no metabolite detected). Monophasic kinetics were observed for the N-glucuronidation of seven substrates by human liver microsomes, which suggests that one enzyme is involved in each metabolic catalysis. No N-glucuronidation was observed for the substrate containing the para-phenyl substituent with the largest electron withdrawing effect, 1-(4-nitrophenyl)imidazole. Linear correlation analyses between apparent microsomal kinetics and substrate physicochemical parameters revealed significant correlations between K m and lipophilicity ( para or log P values) and between V max /K m and both electronic properties ( para value) and pKa.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

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Quaternary Ammonium-Linked Glucuronidation of 1-Substituted Imidazoles by Liver Microsomes: Interspecies Differences and Structure-Metabolism Relationships

Vashishtha¹,

Hawes²,

McCann³

et al. 2002

Drug Metabolism and Disposition

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“…The capacity of hepatocytes to form metabolites decreases with time in culture; as expected from measurement of drug metabolizing enzymes, it drops much earlier in rodent hepatocytes than in their human counterparts (198). For example, no change in the metabolic rate and percentage of the two major metabolites formed from ketotifen was observed in human hepatocytes during the first 4 days of culture; the metabolic rate markedly decreased in rat hepatocyte cultures between day 2 and day 4.…”

Section: However Survival and Metabolic Compe-mentioning

confidence: 85%

Liver cell models in in vitro toxicology.

Guillouzo

1998

Environ Health Perspect

300

125

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In vitro liver preparations are increasingly used for the study of hepatotoxicity of chemicals. In recent years their actual advantages and limitations have been better defined. The cell models, slices, and mainly primary hepatocyte cultures, appear to be the most powerful in vitro systems, as liver-specific functions and responsiveness to inducers are retained either for a few days or several weeks depending on culture conditions. Maintenance of phase and phase 11 xenobiotic metabolizing enzyme activities allows various chemical investigations to be performed, including determination of kinetic parameters, metabolic profile, interspecies comparison, inhibition and induction effects, and drug-drug interactions. In vitro liver cell models also have various applications in toxicology: screening of cytotoxic and genotoxic compounds, evaluation of chemoprotective agents, and determination of characteristic liver lesions and associated biochemical mechanisms induced by toxic compounds. Extrapolation of the results to the in vivo situation remains a matter of debate. Presently, the most convincing applications of liver cell models are the studies on different aspects of metabolism and mechanisms of toxicity. For the future, there is a need for better culture conditions and differentiated hepatocyte cell lines to overcome the limited availability of human liver tissues. In addition, strategies for in vitro analysis of potentially toxic chemicals must be better defined. Environ Health Perspect 106(Suppl 2):511-532 (1998). http.//ehpnetl.niehs.nih.gov/docs/1998/Suppl-2/51 1-532guillouzo/abstract.html

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“…In addition, transporters such as BSEP and NTCP, repressed in response to PB and RIF in human hepatocytes, were not affected in mice exposed to CAR or PXR agonists (Wagner et al, 2005); similarly, MDR1, up-regulated by PB in human hepatocytes, was not affected by this chemical in rat counterparts (Courtois et al, 2002). The reasons for these discrepancies are unclear, but they may be linked to interspecies differences occurring for liver-detoxifying proteins (Le Bigot et al, 1987).…”

Section: Jigorel Et Almentioning

confidence: 99%

Differential Regulation of Sinusoidal and Canalicular Hepatic Drug Transporter Expression by Xenobiotics Activating Drug-Sensing Receptors in Primary Human Hepatocytes

Jigorel

Vée²,

Boursier-Neyret³

et al. 2006

Drug Metabolism and Disposition

280

196

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ABSTRACT:Sinusoidal and canalicular hepatic drug transporters constitute key factors involved in drug elimination from liver. Regulation of their expression via activation of xenosensors, such as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and nuclear factor E2-related factor 2 (Nrf2), remains incompletely characterized. The present study was therefore designed to carefully analyze expression of major drug transporters in primary human hepatocytes exposed to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) (an AhR activator), rifampicin (RIF) (a PXR activator), phenobarbital (PB) (a CAR activator), and oltipraz (OPZ) (a Nrf2 activator), using mainly reverse transcription-real time polymerase chain reaction assays. With a threshold corresponding to a 1.5-fold factor change in mRNA levels, observed in at least three of seven independent human hepatocyte cultures, efflux transporters such as MDR1, MRP2 and BCRP were up-regulated by PB, RIF, and OPZ, whereas MRP3 was induced by OPZ and RIF. MDR1 and BCRP expression was also increased by TCDD-and RIF-augmented mRNA levels of the influx transporter OATP-C. Bile acid transporters, i.e., bile salt export pump and Na ؉ -taurocholate cotransporting polypeptide, and the sinusoidal transporter, OAT2, were down-regulated by all the tested chemicals. Influx transporters such as OCT1, OATP-B, and OATP8 were repressed by PB and TCDD. PB also decreased MRP6 expression, whereas mRNA levels of OCT1 and OATP8 were downregulated by RIF and OPZ, respectively. Taken together, these data establish a complex pattern of transporter regulation by xenobiotics in human hepatocytes, in addition to interindividual variability in responsiveness. This may deserve further attention with respect to drug-drug interactions and adverse effects of hepatic drugs.Hepatic drug transporters constitute important factors in the hepatobiliary elimination of xenobiotics (Chandra and Brouwer, 2004). They belong to the solute carrier (SLC) or the ATP-binding cassette (ABC) superfamilies of transporters (Schinkel and Jonker, 2003). SLC transporters, especially organic cation transporter 1 (OCT1/ SLC22A1) (Jonker and Schinkel, 2004), organic anion-transporting polypeptides (OATP-B/SLCO2B1, OATP-C/SLCO1B1, and OATP8/ SLCO1B3) (Hagenbuch and Meier, 2003), and organic anion transporter 2 (OAT2/SLC22A7) (Kobayashi et al., 2005), located at the sinusoidal membrane of hepatocytes, mediate the uptake of endogenous and foreign compounds from blood. Canalicular ABC transporters, such as P-glycoprotein (ABCB1) encoded by multidrug resistance 1 (MDR1) gene, multidrug resistance protein 2 (MRP2/ABCC2), MRP6 (ABCC6), and breast cancer resistance protein (BCRP/ ABCG2), are involved in secretion of drugs or their metabolites into bile (Schinkel and Jonker, 2003;Fardel et al., 2005). The efflux pump MRP3 (ABCC3) is located at the sinusoidal pole, where it is thought to mediate secretion of drug metabolites into the bloodstream for subsequent urinary elimination (Zelcer e...

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Species differences in metabolism of ketotifen in rat, rabbit and man: Demonstration of similar pathways and in cultured hepatocytes

Cited by 70 publications

References 13 publications

Quaternary Ammonium-Linked Glucuronidation of 1-Substituted Imidazoles by Liver Microsomes: Interspecies Differences and Structure-Metabolism Relationships

Quaternary Ammonium-Linked Glucuronidation of 1-Substituted Imidazoles by Liver Microsomes: Interspecies Differences and Structure-Metabolism Relationships

Liver cell models in in vitro toxicology.

Differential Regulation of Sinusoidal and Canalicular Hepatic Drug Transporter Expression by Xenobiotics Activating Drug-Sensing Receptors in Primary Human Hepatocytes

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