Chronopharmacokinetics of Cyclosporine A in the Wistar rat following oral administration

Malmary, Marie-France; Kabbaj, Karima; Labat, Christian; Batalla, A.; Houti, I; Moussamih, Samya; Oustrin, J

doi:10.1007/bf03188782

Cited by 13 publications

(3 citation statements)

References 18 publications

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“…The time-dependent effects of calcineurin inhibitors might also be related to changes in pharmacokinetics, which have been described for both CsA and tacrolimus (Baraldo and Furlanut, 2006;Cipolle et al, 1988;Malmary et al, 1992;Ohlman et al, 1993). However, since we have found similar effects for i.p.…”

Section: Discussionsupporting

confidence: 73%

Immunosuppressant calcineurin inhibitors phase shift circadian rhythms and inhibit circadian responses to light

Katz

Simonetta

Ralph

et al. 2008

Pharmacology Biochemistry and Behavior

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Section: Discussionsupporting

confidence: 73%

Immunosuppressant calcineurin inhibitors phase shift circadian rhythms and inhibit circadian responses to light

Katz

Simonetta

Ralph

et al. 2008

Pharmacology Biochemistry and Behavior

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“…In fact, some investigators reported the possibility of withinday variations in microsomal hepatic enzymes activity. ', 34, 35 However, our results suggest little circadian variations since the AUCs were similar for the periods of activity and rest.…”

Section: Discussionmentioning

confidence: 53%

Circadian Variations in the Pharmacokinetics of a New Microemulsion Formulation of Cyclosporine in Cardiac Transplant Recipients

Châteauvert,

Côté

1998

Pharmacotherapy

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We attempted to characterize circadian variations in pharmacokinetic parameters of a new formulation of cyclosporine (CsA) in nine cardiac allograft recipients. A secondary objective was to determine the sampling time that correlated best with exposure of patients to the drug. This was a two‐period study with each period lasting 12 hours. All patients received two equal doses of a new microemulsion of CsA 12 hours apart. Blood samples to measure drug levels were obtained at administration and 1, 2, 3, 4, 6, 9, and 12 hours after each dose. We found no statistically significant difference in pharmacokinetic parameters (areas under the curve, minimum blood concentration, oral clearance) measured during the day and during the night. However, maximum blood concentrations during the day were 30% higher than those at night (p<0.05). We found a good correlation between minimum concentrations in the morning and overall exposure of patients to CsA (r = 0.89). This new microemulsion appears to have few circadian variations of blood concentrations in cardiac transplant recipients. The clinical significance of higher maximum blood concentration during daytime remains to be elucidated. Our results support the most widely accepted method for monitoring CsA, which is based on minimum concentrations in the morning.

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“…8,12) This dose was comparable to an usual dose of CsA in human (i.e., 175 mg/body). In order to avoid possible chronopharmacokinetic changes, 14) the administration was always performed at around 10:30 a.m. Blood samples (10 ml) were collected from the tail artery at designated time intervals, solubilized using a Soluene350 ® : propanol mixture (1 : 1, v/v) and decolorized by the addition of 30% H 2 O 2 .…”

Section: Chemicals and Dosage Formsmentioning

confidence: 99%

Limited Role of P-Glycoprotein in the Intestinal Absorption of Cyclosporin A

Lee

Chung

Shim

2005

Biological & Pharmaceutical Bulletin

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Cyclosporin A (CsA), a powerful immunosuppressive agent, is orally administered to prevent rejection in new organ transplants and to treat a variety of autoimmune diseases.1) The intestinal absorption of CsA following oral administration is poor (typically 20-50%) and varies greatly among patients, 2) owing to its relatively high molecular weight (1202.6), poor solubility in aqueous fluids, 3) site-specific absorption in the small intestine, 4) and intestinal firstpass metabolism by the Cyp450 system. 5) Furthermore, Pglycoprotein (P-gp), an ATP-dependent efflux transporter, has been proposed as a factor in the poor absorption of CsA [6][7][8] via various experiments, including the effect of single nucleotide polymorphism of P-gp 9) and P-gp related herb-CsA drug interaction. 10) However, little is known to date concerning the quantitative contribution of P-gp to the absorption of CsA. Only a limited number of experiments, such as an in vitro transport study employing the Caco-2 cell system, 11) a speculative in vivo experiment in mice 12) and human clinical trials, 13) have been reported. Thus, the quantitative contribution of P-gp to the absorption of CsA was investigated in the present study. For this purpose, the absorption of CsA in P-gp knockout (Mdr1a/1b knockout) mice and wildtype mice was compared, and the concentration dependency of the transport of CsA across Caco-2 cell monolayers was investigated. MATERIALS AND METHODS Chemicals and Dosage Forms3 H-CsA (Amersham, Okaville, ON, U.S.A.), CsA (Galena Co., Czecho) and Neoral ® (a CsA microemulsion by Norvatis Pharma AG, Basle, Switzerland) were used. 3 H-CsA was diluted with the Neoral ® solution in saline to give a specific activity of 10 mCi/ml. All other chemicals were of reagent grade and were used without further purification.Animal Experiments P-gp knockout (Mdr1a/1b knockout) mice (Tarconic, U.S.A.) and wild-type control, FVB mice, weighing 28Ϯ5 g (9-18 weeks of age), were used in all experiments. For the pharmacokinetic study, CsA (as Neoral ® solution, 1 mg/kg) was intravenously administered to mice via the tail vein or orally.8,12) This dose was comparable to an usual dose of CsA in human (i.e., 175 mg/body). In order to avoid possible chronopharmacokinetic changes, 14) the administration was always performed at around 10:30 a.m. Blood samples (10 ml) were collected from the tail artery at designated time intervals, solubilized using a Soluene350 ® : propanol mixture (1 : 1, v/v) and decolorized by the addition of 30% H 2 O 2 . Brain was removed 24 h after the each administration, and solubilized in a similar manner. Total radioactivity was determined by liquid scintillation counting (LS 6000SE; Beckman Coulter, Fullerton, CA, U.S.A.), and used for the calculation of blood and brain concentration of CsA.The area under the blood CsA concentration from time 0 to 24 h after administration (AUC 0-24 ) was determined by the standard log-linear trapezoidal rule. The apparent absolute oral bioavailability (F, %) was calculated by comparing the AUC 0-...

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Chronopharmacokinetics of Cyclosporine A in the Wistar rat following oral administration

Cited by 13 publications

References 18 publications

Immunosuppressant calcineurin inhibitors phase shift circadian rhythms and inhibit circadian responses to light

Immunosuppressant calcineurin inhibitors phase shift circadian rhythms and inhibit circadian responses to light

Circadian Variations in the Pharmacokinetics of a New Microemulsion Formulation of Cyclosporine in Cardiac Transplant Recipients

Limited Role of P-Glycoprotein in the Intestinal Absorption of Cyclosporin A

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