Permeability and absorption of leuprolide from various intestinal regions in rabbits and rats

Zheng, Yuqun; Qiu, Yihong; Lu, Mou-Ying Fu; Hoffman, Daniël J.; Reiland, Thomas L.

doi:10.1016/s0378-5173(99)00146-5

Cited by 39 publications

(14 citation statements)

References 11 publications

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“…A variety of in-vitro approaches have been used to assess the transport and permeation characteristics of drugs administered by different routes, such as permeability across the skin for topical formulations and permeability across the intestine, colon and jejunum for orally administered drugs [36]. Recently, dendrimers have been considered for topical applications to the vaginal and cervical mucosa as antimicrobicidal agents[16-19].…”

Section: Resultsmentioning

confidence: 99%

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Transport and biodistribution of dendrimers across human fetal membranes: Implications for intravaginal administration of dendrimer-drug conjugates

et al. 2010

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Dendrimers are emerging as promising topical antimicrobial agents, and as targeted nanoscale drug delivery vehicles. Topical intravaginal antimicrobial agents are prescribed to treat the ascending genital infections in pregnant women. The fetal membranes separate the extra-amniotic space and fetus. The purpose of the study is to determine if the dendrimers can be selectively used for local intravaginal application to pregnant women without crossing the membranes into the fetus. In the present study, the transport and permeability of PAMAM (poly(amidoamine)) dendrimers, across human fetal membrane (using a side-by-side diffusion chamber), and its biodistribution (using immunofluorescence) are evaluated ex-vivo. Transport across human fetal membranes (from the maternal side) was evaluated using Fluorescein (FITC), an established transplacental marker (positive control, size~ 400 Da) and fluorophore-tagged G4-PAMAM dendrimers (~ 16 kDa). The fluorophore-tagged G4-PAMAM dendrimers were synthesized and characterized using 1H NMR, MALDI TOF-MS and HPLC analysis. Transfer was measured across the intact fetal membrane (chorioamnion), and the separated chorion and amnion layers. Over a five hour period, the dendrimer transport across all the three membranes was less than < 3 %, whereas the transport of FITC was relatively fast with as much as 49% transport across the amnion. The permeability of FITC (7.9 × 10-7 cm2/s) through the chorioamnion was 7-fold higher than that of the dendrimer (5.8 × 10-8 cm2/s). The biodistribution showed that the dendrimers were largely present in interstitial spaces in the decidual stromal cells and the chorionic trophoblast cells (in 2.5 to 4 h) and surprisingly, to a smaller extent internalized in nuclei of trophoblast cells and nuclei and cytoplasm of stromal cells. Passive diffusion and paracellular transport appear to be the major route for dendrimer transport. The overall findings further suggest that entry of drugs conjugated to dendrimers would be restricted across the human fetal membranes when administered topically by intravaginal route, suggesting new ways of selectively delivering therapeutics to the mother without affecting the fetus.

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Section: Resultsmentioning

confidence: 99%

“…The transport of molecules across the membranes occurs as a result of passive diffusion or active transport [36]. The passive diffusion differs from the active process such that the passive diffusion of the compound through the cell membrane is dependant on the concentration gradient with a constant permeability coefficient.…”

Section: Resultsmentioning

confidence: 99%

Transport and biodistribution of dendrimers across human fetal membranes: Implications for intravaginal administration of dendrimer-drug conjugates

et al. 2010

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“…GnRH receptor agonists currently in clinical use (e.g., leuprolide) are superior to the native hormone (GnRH) in terms of potency because of their high receptor affinity and improved proteolytic stability (Berger et al, 1991). However, GnRH analogs are still susceptible to the action of proteolytic enzymes (Haviv et al, 1992) and have limited absorption (Zheng et al, 1999) and low bioavailability (Adjei et al, 1993). As a consequence, these peptides are administered intramuscularly or subcutaneously and as depot formulations (Sennello et al, 1986;Perez-Marreno et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a Stable Gonadotropin-Releasing Hormone Analog in Mice for the Treatment of Endocrine Disorders and Prostate Cancer

Κάτσιλα

Balafas²,

Liapakis³

et al. 2010

J Pharmacol Exp Ther

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Gonadotropin-releasing hormone (GnRH) receptor agonists have wide clinical applications including the treatment of prostate cancer and endocrine disorders. However, such agonists are characterized by poor pharmacokinetic properties, often requiring repeated administration or special formulations. Therefore, the development of novel peptide analogs with enhanced in vivo stability could potentially provide therapeutic alternatives. The pharmacological evaluation of a bioactive peptide [Des-Gly 10 ,Tyr 5 (OMe),D-Leu 6 ,Aze-NHEt 9 ]GnRH, analog 1, is presented herein and compared with leuprolide. Peptide stability was evaluated using mouse kidney membrane preparations, followed by a liquid chromatography-tandem mass spectrometry-based approach that afforded identification and quantification of its major metabolites. The analog was significantly more stable in vitro in comparison with leuprolide. In vitro and in vivo stability results correlated well, encouraging us to develop a clinically relevant pharmacokinetic mouse model, which facilitated efficacy measurements using testosterone as a biomarker. Analog 1, an agonist of the GnRH receptor with a binding affinity in the nanomolar range, caused testosterone release in mice that was acutely dose-dependent, an effect blocked by the GnRH receptor antagonist cetrorelix. Repeated dosing studies in mice demonstrated that analog 1 was well tolerated and had potency similar to that of leuprolide, based on plasma and testis testosterone reduction and histopathological findings. Analog 1 also shared with leuprolide similar significant antiproliferative activity on androgen-dependent prostate cancer (LNCaP) cells. On the basis of pharmacokinetic advantages, we expect that analog 1 or analogs based on this new design will be therapeutically advantageous for the treatment of cancer and endocrine disorders.

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“…Preferential absorption of drugs has also been demonstrated for different sites of the GI tract. For example leuprolide shows absorption variability throughout the GI tract in rats, with maximum absorption available in the colon 39…”

Section: Discussionmentioning

confidence: 99%

A pharmacoscintigraphic study of three time-delayed capsule formulations in healthy male volunteers

McConville

Hodges

Jones

et al. 2009

Journal of Pharmaceutical Sciences

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Permeability and absorption of leuprolide from various intestinal regions in rabbits and rats

Cited by 39 publications

References 11 publications

Transport and biodistribution of dendrimers across human fetal membranes: Implications for intravaginal administration of dendrimer-drug conjugates

Transport and biodistribution of dendrimers across human fetal membranes: Implications for intravaginal administration of dendrimer-drug conjugates

Evaluation of a Stable Gonadotropin-Releasing Hormone Analog in Mice for the Treatment of Endocrine Disorders and Prostate Cancer

A pharmacoscintigraphic study of three time-delayed capsule formulations in healthy male volunteers

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