Genetic Basis of Inter- and Intrastrain Differences in Diazepam p-Hydroxylation in Rats

Sakai, Noriaki; Saito, Katsuharu; Sakamoto, Kentaro Q.; Ishizuka, Mayumi; Fujita, Shoichi

doi:10.1124/dmd.108.024273

Cited by 6 publications

(2 citation statements)

References 11 publications

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“…For example, it may well be that the very ingenuity of experimental scientists in mimicking human diseases in animals blinds them to the fact that underlying the induced disorder is a non-human physiology. There is a wealth of evidence, in a wide range of physiological systems, that even closely related species can use quite different biochemical pathways to achieve the same biological end (8)(9)(10)(11)(12), and even within species, choice of strain can have a profound influence (9,10,13,14).…”

Section: Shortcomings Of Animal-based Approachesmentioning

confidence: 99%

Drug Discovery and Development Tomorrow — Changing the Mindset

Coleman

2009

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Today's drug discovery and development paradigm is not working, and something needs to be done about it. There is good reason to believe that a move away from reliance on animal surrogates for human subjects in the Pharma Industry's R&D programmes could provide an important step forward. However, no serious move will be made in that direction until there is some hard evidence that it will be rewarded with improved productivity outcomes. The Safer Medicines Trust are proposing that a study be undertaken, involving a range of drugs that have been approved for human use, but have subsequently proved to have limitations in terms of safety and/or efficacy. The aim is to determine the efficiency of a battery of human-based test methods to identify a compound's safety and efficacy profiles, and to compare this with that of the more traditional, largely animal-based methods that were employed in their original development. Should such an approach prove more reliable, the authorities will be faced with important decisions relating to the role of human biological test data in regulatory submissions, while the Pharma Industry will be faced with the key logistical issue of how to acquire the human biomaterials necessary to make possible the routine application of such test methods.

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Section: Shortcomings Of Animal-based Approachesmentioning

confidence: 99%

Drug Discovery and Development Tomorrow — Changing the Mindset

Coleman

2009

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“…In rats, the very low expression level of CYP2D2 in female Dark Agouti rats allowed them to be used as the model for the CYP2D6 poor metabolizer phenotype in humans (Yamamoto et al, 1998;Schulz-Utermoehl et al, 1999). CYP2D3 has also been shown to cause genetic polymorphisms in the p-hydroxylation of diazepam in Wistar rats (Saito et al, 2004;Sakai et al, 2005Sakai et al, , 2009.…”

Section: Introductionmentioning

confidence: 99%

Interindividual Variations in Metabolism and Pharmacokinetics of 3-(6-Methylpyridine-3-yl-sulfanyl)-6-(4H-[1,2,4]triazole-3-yl-sulfanyl)-N-(1,3-thiazole-2-yl)-2-pyridine carboxamide, a Glucokinase Activator, in Rats Caused by the Genetic Polymorphism of CYP2D1

Hasegawa¹,

Eiki²,

Chiba³

2014

Drug Metabolism and Disposition

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3-(6-Methylpyridine-3-yl-sulfanyl)-6-(4H-[1,2,4]triazole-3-yl-sulfanyl)-N-(1,3-thiazole-2-yl)-2-pyridine carboxamide (Cpd-D) is a novel glucokinase activator that is being developed for the treatment of type 2 diabetes. Large interindividual variations were observed in the pharmacokinetics of Cpd-D in male Sprague-Dawley (SD) rats, which were subsequently divided into two phenotypes; >6-fold longer terminal-phase half-life and ∼10-fold larger AUC 0-' values were observed in slow metabolizers (SM) than in fast metabolizers (FM) after the oral administration of Cpd-D. The thiohydantoic acid analog (M2) was the predominant metabolite detected in the urine, bile, and plasma after the oral administration of [ 14 C]Cpd-D to the FM phenotypes of bile-duct cannulated SD rats. The liver microsomes prepared from FM phenotyped rats extensively formed M2 with the highest affinity (K m = 0.09 mM) and largest V max /K m value in primary metabolism, whereas those from SM phenotypes had little capacity to form M2. Of the rat cytochrome P450 isoforms tested, the formation of M2 was only catalyzed by recombinant CYP2D1. Sequence substitutions (418A/421C and 418G/421T) were detected in the CYP2D1 gene and were designated F and S alleles, respectively. The genotypephenotype correlation analysis indicated that two S alleles were homozygous (S/S) in the SM phenotypes, whereas the FM phenotypes were either homozygous for the F-alleles (F/F) or heterozygous (F/S). These results indicated that the CYP2D1 polymorphism caused by nucleotide substitutions (418A/421C versus 418G/421T) was responsible for interindividual variations leading to the polymorphism in the major metabolism and pharmacokinetics of Cpd-D in male SD rats.

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Comparative and Veterinary Pharmacogenomics

Mosher

Court

2010

Comparative and Veterinary Pharmacology

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Pharmacogenomics is the study of the impact of genetic variation on drug effects, with the ultimate goal of achieving "personalised medicine". Since the completion of the Human Genome Project, great strides have been made towards the goal of personalised dosing of drugs in people, as exemplified by the development of gene-guided dosing of the anticoagulant drug, warfarin. Although the pharmacogenomics of domestic animals is still at an early stage of development, there is great potential for advances in the coming years as the direct result of complete genome sequences currently being derived for many of the species of significance to veterinary and comparative medicine. This sequence information is being used to discover sequence variants in candidate genes associated with altered drug response, as well as to develop whole genome high density single nucleotide polymorphism arrays for genotype-phenotype linkage analysis. This review summarises the current state of veterinary pharmacogenomics research, including drug response variability phenotypes with either known genetic aetiology or strong circumstantial evidence for genetic involvement. Polymorphisms and rarer gene variants affecting drug disposition (pharmacokinetics) and drug effect (pharmacodynamics) are discussed. In addition to providing the veterinary clinician with useful information for the practise of therapeutics, it is envisaged that the increasing knowledge base will also provide a resource for individuals involved in veterinary and comparative biomedical research.

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Genetic Basis of Inter- and Intrastrain Differences in Diazepam p-Hydroxylation in Rats

Cited by 6 publications

References 11 publications

Drug Discovery and Development Tomorrow — Changing the Mindset

Drug Discovery and Development Tomorrow — Changing the Mindset

Interindividual Variations in Metabolism and Pharmacokinetics of 3-(6-Methylpyridine-3-yl-sulfanyl)-6-(4H-[1,2,4]triazole-3-yl-sulfanyl)-N-(1,3-thiazole-2-yl)-2-pyridine carboxamide, a Glucokinase Activator, in Rats Caused by the Genetic Polymorphism of CYP2D1

Comparative and Veterinary Pharmacogenomics

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