Physiologic modeling of cyclosporin kinetics in rat and man

Bernareggi, A.; Rowland, Malcolm

doi:10.1007/bf01062191

Cited by 159 publications

(101 citation statements)

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“…1) [the unbound EC 50 value was computed using the reported CsA fraction unbound of 6% in the rat (Bernareggi and Rowland, 1991;Hsiao et al, 2006)]. In the presence of complete inhibition of P-gp, the maximal increase in verapamil accumulations in the LLCPK1-MDR1 cells is much less (ϳ150% increase, Fig.…”

Section: Resultsmentioning

confidence: 99%

In Vitro-to-in Vivo Prediction of P-glycoprotein-Based Drug Interactions at the Human and Rodent Blood-Brain Barrier

Hsiao

Bui

et al. 2007

Drug Metab Dispos

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ABSTRACT:In vitro inhibition of P-glycoprotein (P-gp) expressed in cells is routinely used to predict the potential of in vivo P-gp drug interactions at the human blood-brain barrier (BBB). The accuracy of such predictions has not been confirmed because methods to quantify in vivo P-gp drug interactions at the human BBB have not been available. With the development of a noninvasive positron emission topography (PET) imaging method by our laboratory to determine P-gp-based drug interactions at the human BBB, an in vitro-in vivo comparison is now possible. Therefore, we developed a high throughput cell-based assay to determine the potential of putative P-gp inhibitors [including cyclosporine A (CsA)] to inhibit (EC 50 ) the efflux of verapamil-bodipy, a model P-gp substrate. LLCPK1-MDR1 cells, expressing recombinant human P-gp, or control cells lacking P-gp (LLCPK1) were used in our assay. Using this assay, quinine, quinidine, CsA, and amprenavir were predicted to be the most potent P-gp inhibitors in vivo at their respective therapeutic maximal unbound plasma concentrations. The in vitro EC 50 of CsA (0.6 M) for P-gp inhibition was virtually the same as our previously determined in vivo unbound EC 50 at the rat BBB (0.5 M). Moreover, at 2.8 M CsA (total blood concentration), our in vitro data predicted an increase of 129% in [11 C]verapamil distribution into the human brain, a value similar to that observed by us (79%) using PET. These data suggest that our high throughput cell assay has the potential to accurately predict P-gp drug interactions at the human BBB.The in vivo importance of P-glycoprotein (P-gp) at the BBB has been well demonstrated by studies in mdr1a/b (Ϫ/Ϫ) mice. For example, compared with the wild-type mouse, in the mdr1a/b (Ϫ/Ϫ) mice, the brain/plasma concentration ratio (or the brain uptake) of the anti-human immunodeficiency virus protease inhibitors is increased 7-to 36-fold and anti-cancer taxanes, paclitaxel, or docetaxel are increased 6-to 28-fold, whereas that of verapamil is increased 8.5-fold (Endres et al., 2006). Similar data have been obtained in mice and rats where P-gp has been chemically ablated with selective inhibitors of P-gp such as PSC833, GF120918, and LY335979 (Lin and Yamazaki, 2003;Endres et al., 2006). For example, the brain/plasma ratio of verapamil is increased 24.1-fold when the rat is pretreated with cyclosporine A (CsA) (Hendrikse and Vaalburg, 2002). Based on these data and others, it has been widely postulated that P-gp plays a vital role in limiting drug distribution at the human BBB and that P-gp-based drug interactions will result in a profound increase in brain concentrations of the affected drugs and, therefore, their CNS efficacy or toxicity.Although rodent studies make a compelling case for the importance of P-gp at the BBB in the CNS distribution of drugs, their ability to predict the magnitude of P-gp-based drug interactions at the human BBB has not been investigated. Due to safety and ethical reasons, it has not been possible to measure in vivo human BB...

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Section: Resultsmentioning

confidence: 99%

In Vitro-to-in Vivo Prediction of P-glycoprotein-Based Drug Interactions at the Human and Rodent Blood-Brain Barrier

Hsiao

Bui

et al. 2007

Drug Metab Dispos

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“…Radioactive counts were corrected for background and decay. The amount of residual blood within each brain sample, expressed as grams of blood per gram of brain, was calculated as the ratio between 51 Cr counts per minute per gram of brain and counts per minute per gram of blood (20). These values were converted into milliliters of blood per gram of tissue using 1 g/ml as the density of blood.…”

Section: Pharmacokinetics Of 125 I-7e3 In Micementioning

confidence: 99%

Investigation of the Influence of FcRn on the Distribution of IgG to the Brain

Garg

Balthasar

2009

AAPS J

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Abstract. It has been suggested that the neonatal Fc receptor (FcRn) is a primary determinant of the distribution of IgG to the brain. In the present report, 125 I-labeled 7E3, a monoclonal IgG1 antibody, was injected intravenously to groups of FcRn-deficient mice and C57BL/6J control mice. Sub-groups of three mice were sacrificed at several time points. Blood and brain tissue were harvested and radioactivity was assessed. Antibody concentrations in brain were corrected for residual blood using 51 Cr-labeled red blood cells. Data were analyzed via WinNonlin, and areas under plasma and tissue concentration vs. time curves (AUCs) were assessed via the Bailer method. The apparent plasma elimination half-life and clearance of 7E3 were 13.61±0.61 days and 6.5±0.10 ml/day/kg in control mice and 0.70±0.05 days and 63.5±2.7 ml/day/kg in the knockout mice. Plasma and brain AUCs (0-10 days) were found to be 3,338.7± 50.4 and 7.46±0.5 nM day in control animals and 781.2±16.6 and 1.65±0.1 nM day in FcRn-deficient animals. There was no significant difference between brain-to-plasma AUC ratios in control and FcRndeficient mice (0.0022±0.00015 vs. 0.0021±0.00011, p=0.3347). Two-way analysis of variance showed no significant differences, at any time point, between brain-to-plasma concentration ratios determined from control and knockout animals. The results suggest that FcRn does not contribute significantly to the "blood-brain barrier" for IgG in mice, and the data suggest that FcRn is not responsible for the low exposure of IgG in the brain relative to plasma.

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“…Organ volumes (V i ) were scaled from published data for a 250-g rat (Bernareggi and Rowland, 1991;Davies and Morris, 1993) using…”

mentioning

confidence: 99%

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

127

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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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Physiologic modeling of cyclosporin kinetics in rat and man

Cited by 159 publications

References 23 publications

In Vitro-to-in Vivo Prediction of P-glycoprotein-Based Drug Interactions at the Human and Rodent Blood-Brain Barrier

In Vitro-to-in Vivo Prediction of P-glycoprotein-Based Drug Interactions at the Human and Rodent Blood-Brain Barrier

Investigation of the Influence of FcRn on the Distribution of IgG to the Brain

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

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