Pharmacokinetics of reversible metabolic systems

Cheng, Haiyung; Jusko, William J.

doi:10.1002/bdd.2510140902

Cited by 36 publications

(26 citation statements)

References 274 publications

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“…The characterization of reversible systems can be achieved only after collecting concentration-time data of parent and metabolite after separate i.v. administration of parent and metabolite (Cheng and Jusko, 1993). No metabolite concentration data were measured in the present study.…”

Section: Discussionmentioning

confidence: 82%

Physiologically Based Pharmacokinetic Modeling of FTY720 (2-Amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in Rats After Oral and Intravenous Doses

Meno‐Tetang¹,

Li²,

Mis³

et al. 2006

Drug Metab Dispos

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129

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ABSTRACT:FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) is a new sphingosine-1-phosphate receptor agonist being developed for multiple sclerosis and prevention of solid organ transplant rejection. A physiologically based pharmacokinetic model was developed to predict the concentration of FTY720 in various organs of the body. Single oral and intravenous doses of FTY720 were administered to male Wistar rats, with blood and tissue sampling over 360 h analyzed by liquid chromatography/ tandem mass spectrometry. A well stirred model (perfusion ratelimited) described FTY720 kinetics in heart, lungs, spleen, muscle, kidneys, bone, and liver, with a permeability rate-limited model being required for brain, thymus, and lymph nodes. Tissue-toblood partition coefficients (R T ) ranged from 4.69 (muscle) to 41.4 (lungs). In lymph nodes and spleen, major sites for FTY720-induced changes in sequestration of lymphocytes, R T values were 22.9 and 34.7, respectively. Permeability-surface area products for brain, thymus, and lymph nodes were 39.3, 122, and 176 ml/min. Intrinsic hepatic clearance was 23,145 l/h/kg for the free drug in blood (f ub 0.000333); systemic clearance was 0.748 l/h/kg and terminal halflife was 23.4 h. The fraction orally absorbed was 71%. The model characterized well FTY720 disposition for this extensive dosing and tissue collection study in the rat. On scaling the model to dogs and humans, good agreement was found between the actual and predicted blood concentration-time profiles. More importantly, brain concentrations in dogs were well predicted from those of the rat. In absolute terms, the predictions were slightly lower than observed values, just under a 1.5-fold deviation, but the model accurately predicted the terminal elimination of FTY720 from the brain. FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) is a new sphingosine-1-phosphate receptor agonist that is being developed for prevention of solid organ transplant rejection (Napoli, 2000). FTY720 exerts its immunomodulatory actions by affecting lymphocyte production (Yagi et al., 2000), trafficking Brinkmann et al., 2000Brinkmann et al., , 2001, infiltration (Yanagawa et al., 2000), and apoptosis (Enosawa et al., 1996;Bohler et al., 2000;Nagahara et al., 2000). The maximum effects of FTY720 on these immune responses are achieved at doses smaller than those producing effects against graft rejection .Regulation of gene expression may also account for pharmacological and toxicological effects of FTY720: for instance, a 26-week pharmacology study in rats using gene chips showed that, at doses of 0.3 and 1.5 mg/kg/day, genes of B and T lymphocyte markers in blood (CD79 and CD3) were down-regulated (Novartis Pharma AG, internal communication).The elimination of FTY720 from the body occurs mainly via metabolism. Two primary pathways metabolize FTY720: 1) phosphorylation at one of its two hydroxy groups (yielding FTY720-P) and 2) hydroxylation at the terminal methyl group (M12) (Novartis Pharma AG, inter...

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Section: Discussionmentioning

confidence: 82%

Physiologically Based Pharmacokinetic Modeling of FTY720 (2-Amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in Rats After Oral and Intravenous Doses

Meno‐Tetang¹,

Li²,

Mis³

et al. 2006

Drug Metab Dispos

Self Cite

129

View full text Add to dashboard Cite

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“…2, includes a dose apportionment independent of the rate constant values (K ap and K am ) with a fraction F p of the dose leading to the parent and a fraction 1-F p leading to the metabolite prior to reach the plasma. Such presystemic formation of an interconversion metabolite is mentioned in the extensive review on reversible metabolic systems from Cheng and Jusko (18). For identifiability purposes, the fraction of dose available after absorption (f) was set to 1.…”

Section: Joint Pharmacokinetic Modelmentioning

confidence: 99%

“…Estimating all PK parameters requires that both the parent drug and the metabolite be given by the intravenous route in addition to the oral administration of the parent compound (18). It results that only "apparent" parameters can be estimated.…”

Section: Joint Pharmacokinetic Modelmentioning

confidence: 99%

Development of a Complex Parent-Metabolite Joint Population Pharmacokinetic Model

Bertrand

Laffont

Chenel

et al. 2011

AAPS J

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Abstract. This study aimed to develop a joint population pharmacokinetic model for an antipsychotic agent in development (S33138) and its active metabolite (S35424) produced by reversible metabolism. Because such a model leads to identifiability problems and numerical difficulties, the model building was performed using the FOCE-I and the Stochastic Approximation Expectation Maximization (SAEM) estimation algorithms in NONMEM and MONOLIX, respectively. Four different structural models were compared based on Bayesian information criteria. Models were first written as ordinary differential equations systems and then in closed form (CF) to facilitate further analyses. The impact of polymorphisms on genes coding for the CYP2C19 and CYP2D6 enzymes, respectively involved in the parent drug and the metabolite elimination were investigated using permutation Wald test. The parent drug and metabolite plasma concentrations of 101 patients were analyzed on two occasions after 4 and 8 weeks of treatment at 1, 3, 6, and 24 h following daily oral administration. All configurations led to a two compartment model with back-transformation of the metabolite into the parent drug and a first-pass effect. The elimination clearance of the metabolite through other processes than back-transformation was decreased by 35% [9-53%] in CYP2D6 poor metabolizer. Permutation tests were performed to ensure the robustness of the analysis, using SAEM and CF. In conclusion, we developed a complex joint pharmacokinetic model adequately predicting the impact of CYP2D6 polymorphisms on the parent drug and its metabolite concentrations through the back-transformation mechanism.

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“…[44], [58] The nonlinear interconversion varies with time and dose. [11], [31], [44], [49], [59][60][61][62] The serum half-life of prednisolone is known to be 2-4 h, [10], [11], [32], [33], [39], [44], [46] and may be influenced by time of day, age, gender, physical exercise, pregnancy, drugs, and several diseases. [14] Prednisolone is cleared from the body primarily by hepatic metabolism by hydroxylation and reduction forming metabolites which conjugate with glucuronic acid and sulfate.…”

Section: Metabolism and Excretionmentioning

confidence: 99%

Biowaiver Monographs for Immediate Release Solid OralDosage Forms: Prednisolone

Vogt

Derendorf

Krämer³

et al. 2007

Journal of Pharmaceutical Sciences

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A project of the International Pharmaceutical Federation FIP, Groupe BCS, www.fip.org. This article reflects the scientific opinion of the authors and not the policies of regulating agencies. AbstractLiterature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.

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Pharmacokinetics of reversible metabolic systems

Cited by 36 publications

References 274 publications

Physiologically Based Pharmacokinetic Modeling of FTY720 (2-Amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in Rats After Oral and Intravenous Doses

Physiologically Based Pharmacokinetic Modeling of FTY720 (2-Amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in Rats After Oral and Intravenous Doses

Development of a Complex Parent-Metabolite Joint Population Pharmacokinetic Model

Biowaiver Monographs for Immediate Release Solid OralDosage Forms: Prednisolone

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