Effect of cyclodextrin concentration on the oral bioavailability of danazol and cinnarizine in rats

Rene Holm, Niels Erik Olesen, Rune Andersen Hartvig, Erling B. Jørgensen, Dorrit B. Larsen, Peter Westh

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Cyclodextrins (CDs) are frequently used as an excipient to enhance the intestinal drug absorption of compounds with a low aqueous solubility. However, there exists an intricate interplay between opposing effects that determine the optimal dosing criterion. These opposing effects are the benefits of circumventing the dissolution time required to dissolve the non-absorbable drug particles in the intestine versus the disadvantage of decreasing the concentration of the drug available to permeate the intestinal membrane if excessive CD concentrations are used. This study investigated whether there is a potential risk of overdosing CDs in aqueous formulations resulting in suboptimal bioavailability. This was done by measuring the in vivo pharmacokinetics of danazol, which has a high affinity for hydroxypropyl-βCD, and cinnarizine, which has a pH-dependent low to medium affinity. Pharmacokinetic studies of danazol in rats showed a significant longer Tmax and decreased Cmax resulting in decreased bioavailability when the CD concentration was increased. No significant difference was seen for any of the pharmacokinetic parameters for cinnarizine as a function of CD dose. The present study thus demonstrates that surplus CD concentrations can have a major effect on the pharmacokinetic profile of one compound and a minor effect on the pharmacokinetic profile of another. This suggests that there are some compounds where the CD excipient should be used with care and others where it can be used without major concerns.
OriginalsprogEngelsk
TidsskriftEuropean Journal of Pharmaceutics and Biopharmaceutics
Vol/bind101
Sider (fra-til)9-14
ISSN0939-6411
DOI
StatusUdgivet - 2016

Citer dette

Holm, Rene ; Olesen, Niels Erik ; Andersen Hartvig, Rune ; Jørgensen, Erling B. ; Larsen, Dorrit B. ; Westh, Peter. / Effect of cyclodextrin concentration on the oral bioavailability of danazol and cinnarizine in rats. I: European Journal of Pharmaceutics and Biopharmaceutics. 2016 ; Bind 101. s. 9-14.
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abstract = "Cyclodextrins (CDs) are frequently used as an excipient to enhance the intestinal drug absorption of compounds with a low aqueous solubility. However, there exists an intricate interplay between opposing effects that determine the optimal dosing criterion. These opposing effects are the benefits of circumventing the dissolution time required to dissolve the non-absorbable drug particles in the intestine versus the disadvantage of decreasing the concentration of the drug available to permeate the intestinal membrane if excessive CD concentrations are used. This study investigated whether there is a potential risk of overdosing CDs in aqueous formulations resulting in suboptimal bioavailability. This was done by measuring the in vivo pharmacokinetics of danazol, which has a high affinity for hydroxypropyl-βCD, and cinnarizine, which has a pH-dependent low to medium affinity. Pharmacokinetic studies of danazol in rats showed a significant longer Tmax and decreased Cmax resulting in decreased bioavailability when the CD concentration was increased. No significant difference was seen for any of the pharmacokinetic parameters for cinnarizine as a function of CD dose. The present study thus demonstrates that surplus CD concentrations can have a major effect on the pharmacokinetic profile of one compound and a minor effect on the pharmacokinetic profile of another. This suggests that there are some compounds where the CD excipient should be used with care and others where it can be used without major concerns.",
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Effect of cyclodextrin concentration on the oral bioavailability of danazol and cinnarizine in rats. / Holm, Rene; Olesen, Niels Erik; Andersen Hartvig, Rune; Jørgensen, Erling B.; Larsen, Dorrit B.; Westh, Peter.

I: European Journal of Pharmaceutics and Biopharmaceutics, Bind 101, 2016, s. 9-14.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Effect of cyclodextrin concentration on the oral bioavailability of danazol and cinnarizine in rats

AU - Holm, Rene

AU - Olesen, Niels Erik

AU - Andersen Hartvig, Rune

AU - Jørgensen, Erling B.

AU - Larsen, Dorrit B.

AU - Westh, Peter

PY - 2016

Y1 - 2016

N2 - Cyclodextrins (CDs) are frequently used as an excipient to enhance the intestinal drug absorption of compounds with a low aqueous solubility. However, there exists an intricate interplay between opposing effects that determine the optimal dosing criterion. These opposing effects are the benefits of circumventing the dissolution time required to dissolve the non-absorbable drug particles in the intestine versus the disadvantage of decreasing the concentration of the drug available to permeate the intestinal membrane if excessive CD concentrations are used. This study investigated whether there is a potential risk of overdosing CDs in aqueous formulations resulting in suboptimal bioavailability. This was done by measuring the in vivo pharmacokinetics of danazol, which has a high affinity for hydroxypropyl-βCD, and cinnarizine, which has a pH-dependent low to medium affinity. Pharmacokinetic studies of danazol in rats showed a significant longer Tmax and decreased Cmax resulting in decreased bioavailability when the CD concentration was increased. No significant difference was seen for any of the pharmacokinetic parameters for cinnarizine as a function of CD dose. The present study thus demonstrates that surplus CD concentrations can have a major effect on the pharmacokinetic profile of one compound and a minor effect on the pharmacokinetic profile of another. This suggests that there are some compounds where the CD excipient should be used with care and others where it can be used without major concerns.

AB - Cyclodextrins (CDs) are frequently used as an excipient to enhance the intestinal drug absorption of compounds with a low aqueous solubility. However, there exists an intricate interplay between opposing effects that determine the optimal dosing criterion. These opposing effects are the benefits of circumventing the dissolution time required to dissolve the non-absorbable drug particles in the intestine versus the disadvantage of decreasing the concentration of the drug available to permeate the intestinal membrane if excessive CD concentrations are used. This study investigated whether there is a potential risk of overdosing CDs in aqueous formulations resulting in suboptimal bioavailability. This was done by measuring the in vivo pharmacokinetics of danazol, which has a high affinity for hydroxypropyl-βCD, and cinnarizine, which has a pH-dependent low to medium affinity. Pharmacokinetic studies of danazol in rats showed a significant longer Tmax and decreased Cmax resulting in decreased bioavailability when the CD concentration was increased. No significant difference was seen for any of the pharmacokinetic parameters for cinnarizine as a function of CD dose. The present study thus demonstrates that surplus CD concentrations can have a major effect on the pharmacokinetic profile of one compound and a minor effect on the pharmacokinetic profile of another. This suggests that there are some compounds where the CD excipient should be used with care and others where it can be used without major concerns.

U2 - 10.1016/j.ejpb.2016.01.007

DO - 10.1016/j.ejpb.2016.01.007

M3 - Journal article

VL - 101

SP - 9

EP - 14

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

ER -