Pharmacokinetics of 1-β-d-arabinofuranosylcytosine (Ara-C) deamination in several species

Dedrick, Robert L.; Forrester, Donald D.; Cannon, Joseph N.; Dareer, Salah M. El; Mellett, L. B.

doi:10.1016/0006-2952(73)90342-0

Cited by 96 publications

(26 citation statements)

References 20 publications

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“…No significant changes were observed in the YM-64227 pharmacokinetic parameters among the C/C homo, C/T hetero, or T/T homo groups after the administration of a single intravenous dose of YM-64227 (dose: 0.1 mg/kg). The CL tot -,blood values for the C/C, C/T, and T/T groups were 2120, 1787, and 2374 ml/h/kg, respectively, which were slightly higher than the canine hepatic blood flow rate (1620 ml/h/kg; Dedrick et al, 1973). The C max after a single oral administration (dose: 0.3 mg/kg) and absolute bioavailability in the T/T group were 17.1 times and 27.2 times higher than those for the C/C group, respectively.…”

Section: Resultsmentioning

confidence: 74%

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THE CANINE CYP1A2 DEFICIENCY POLYMORPHISM DRAMATICALLY AFFECTS THE PHARMACOKINETICS OF 4-CYCLOHEXYL-1-ETHYL-7-METHYLPYRIDO[2,3-D]-PYRIMIDINE-2-(1H)-ONE (YM-64227), A PHOSPHODIESTERASE TYPE 4 INHIBITOR

et al. 2006

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ABSTRACT:In a previous study, it was shown that the novel canine single nucleotide polymorphism (SNP) CYP1A2 1117C>T yields an inactive enzyme. In this study, the effect that this SNP has on the pharmacokinetics of 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227) was investigated. Plasma concentrations of the unchanged drug and five of its metabolites (MM-1 to MM-5) were determined after either intravenous or oral administration of YM-64227 to genotyped dogs (C/C, C/T, and T/T groups). Liver microsomes were prepared from these dogs to determine the in vitro metabolic clearance of YM-64227. After a single oral administration, the maximum plasma concentration and absolute bioavailability of YM-64227 in the T/T group were 17.1 times and 27.2 times higher than those in the C/C group, respectively, whereas the pharmacokinetics of YM-64227 after intravenous administration were not affected by genotype. The metabolic profiles in the T/T group were quite distinct from the others; i.e., the main metabolite was MM-2 in the C/C group, whereas MM-1 and MM-5 were the main metabolites in the T/T group. The formation clearances of MM-2 and MM-3 in the microsomes derived from T/T type dogs were significantly lower, whereas those of MM-1, MM-4, and MM-5 were not affected. A statistically significant correlation was observed between the in vivo and in vitro metabolic intrinsic clearances (r ‫؍‬ 0.82, p < 0.001). The canine CYP1A2 1117C>T SNP proved to be responsible for a substantial portion of the interindividual variability in the pharmacokinetics of YM-64227.Cytochrome P450 (P450) is a superfamily of enzymes that plays an important role in the oxidative metabolism of a wide variety of xenobiotics as well as endogenous compounds (Nelson et al., 1996). The metabolic activity of P450 is affected by several factors such as inhibition by concomitant drugs, induction, and genetic polymorphism (Pelkonen et al., 1998). The P450 polymorphisms have been investigated extensively in clinical settings, and it is well known that mutated alleles of CYP2C9, CYP2C19, and CYP2D6 cause altered plasma concentrations, which might in turn cause unforeseeable adverse reactions (Kagimoto et al., 1990;Sullivan-Klose et al., 1996;Furuta et al., 1999).A large number of P450 cDNA clones have been isolated, sequenced, and extensively studied in humans, mice, and rats (http:// drnelson.utmem.edu/CytochromeP450.html). On the other hand, only a few studies on canine P450 cDNAs have been conducted, although dogs are used extensively in pharmacological research and drug safety assessment studies. At present, a variety of canine P450 enzymes such et al., 1991;Fraser et al., 1997) have been cloned and sequenced. Although gene analysis has revealed that some of these P450s have variants, no obvious change in the plasma concentration of drug associated with single nucleotide polymorphisms (SNPs) has been reported for dogs. In fact, only a few studies have shown the possibility that interindividual variations in the pharmacokinetics of so...

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Section: Resultsmentioning

confidence: 74%

“…CL h was then calculated from eq. 1, using a Q h value of 1620 ml/h/kg (Bischoff et al, 1971;Dedrick et al, 1973;Montandon et al, 1975) and assuming that F a was 1.0 and CL r was 0.0. The R B value of YM-64227 was 0.66 in dogs (estimated from this study).…”

Section: Methodsmentioning

confidence: 99%

THE CANINE CYP1A2 DEFICIENCY POLYMORPHISM DRAMATICALLY AFFECTS THE PHARMACOKINETICS OF 4-CYCLOHEXYL-1-ETHYL-7-METHYLPYRIDO[2,3-D]-PYRIMIDINE-2-(1H)-ONE (YM-64227), A PHOSPHODIESTERASE TYPE 4 INHIBITOR

et al. 2006

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“…The renal excretion of the nucleoside analogue 1-β-Darabinofuranosylcytosine (Ara-C) in several species was found to be correlated to body weight (exponent = 0.8) (15). The slope of this relationship was very similar to the slope relating inulin clearance, an exclusively glomerular process, to species body weight.…”

Section: Rate Of Filtrationmentioning

confidence: 82%

Issues Related to the Use of Canines in Toxicologic Pathology—Issues With Pharmacokinetics and Metabolism

Tibbitts

2003

Toxicol Pathol

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The dog is a commonly used animal model by virtue of its size, well-characterized physiology, and ease of handling. For these reasons and others, dogs are also useful in pharmacokinetic and metabolism studies during the development of both human and veterinary pharmaceutical products. In comparison with humans, or with other animals, dogs have some unique physiologic attributes that can affect the disposition of drugs. Species differences in gastrointestinal physiology, metabolism, renal function, and protein binding can affect the correlation of the pharmacokinetics and toxicology of dogs with those of other species. With the use of relevant examples, this article will provide an introduction to characteristics of dog physiology and their impact on pharmacokinetics, metabolism, drug disposition, toxicity, and dose selection.

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“…models that were based on the pioneering work of Bischoff and Dedrick on thiopental pharmacokinetics (74) who applied concepts of process analysis and simulation derived from chemical engineering (75) to drug pharmacokinetics. This work has been expanded from the initial flow-limited models (76) to include membrane-limited models (reviewed in 46), as well as biotransformations (77), biliary secretion (78), and drug interactions (79). Both the approach of Bischoff and Dedrick and our approach have sought to develop global models in which compartments and fluxes have anatomical meanings.…”

Section: Resultsmentioning

confidence: 99%

Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.

Hofmann¹,

Molino²,

Milanese³

et al. 1983

J. Clin. Invest.

108

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A B S T R A C T A multicompartmental pharmacokinetic model based on physiological principles, experimental data, and the standard mathematical principles of compartmental analysis has been constructed that fully describes the metabolism and enterohepatic cycling in man of cholic acid, a major bile acid. The model features compartments and linear transfer coefficients. The compartments are aggregated into nine spaces based on physiological considerations (liver, gallbladder, bile ducts, jejunum, ileum, colon, portal blood, sinusoidal blood, and general circulation). The transfer coefficients are also categorized according to function: flow, i.e., emptying of gallbladder or intestinal spaces, and circulation of the blood; biotransformation, i.e., conjugation, deconjugation, or dehydroxylation; and transport, i.e., active or passive transport. The model is made time dependent by introducing meals, which trigger discrete increases in gallbladder emptying and intestinal flow. Each space contains three compartments. For cholic acid, these are unconjugated cholic acid, cholylglycine, and cholyltaurine. The model was then used with all existing experimental data to simulate cholic acid metabolism in healthy man over a 24-h period. Satisfactory agreement was obtained between simulated and experimental results for serum bile acid levels, hepatic bile acid secretion, and bile acid secretion into the intestine. The model was also used to classify 16 clinical instances in which the enterohepatic circulation of bile acids is altered

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Pharmacokinetics of 1-β-d-arabinofuranosylcytosine (Ara-C) deamination in several species

Cited by 96 publications

References 20 publications

THE CANINE CYP1A2 DEFICIENCY POLYMORPHISM DRAMATICALLY AFFECTS THE PHARMACOKINETICS OF 4-CYCLOHEXYL-1-ETHYL-7-METHYLPYRIDO[2,3-D]-PYRIMIDINE-2-(1H)-ONE (YM-64227), A PHOSPHODIESTERASE TYPE 4 INHIBITOR

THE CANINE CYP1A2 DEFICIENCY POLYMORPHISM DRAMATICALLY AFFECTS THE PHARMACOKINETICS OF 4-CYCLOHEXYL-1-ETHYL-7-METHYLPYRIDO[2,3-D]-PYRIMIDINE-2-(1H)-ONE (YM-64227), A PHOSPHODIESTERASE TYPE 4 INHIBITOR

Issues Related to the Use of Canines in Toxicologic Pathology—Issues With Pharmacokinetics and Metabolism

Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.

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