- Email: [email protected]
Validation of a dilation hypothesis in the anaesthetised rat
S85
339
331 dttermlnatiottofftw radkal uvengeta by. superoxIdediamtttw blaamaor
In v&m
L. ccmputcll4 G. Pavetn.M.‘IhnuKlti Dcpo#mcntoJChemhy _ Universify ofRome “LaSqLmd’ P.lc Aldo Mom 5 - 00185 Rm (lX4Ll.4)
HYPOTHESIS IN THE VALIDATION OF A DILATION ANAESTHETISED RAT Amanda Malcolm Rowiand Schoolof Pharmacy andPharmacetiical Sciences Unwerstyof Manchester. Ml3 QPL. UK. an extensive program to characterise paracellular As part of absorption, studies have been performed in the in situ perfused rat jejunum tith the aim of predicting in viva oral bioavailability. Absorption of “C-PEG 400 oligomen and ‘H-D peptide probes was assessed from a recirculating isotonic media, over a period of 1 hour by collection and HPLC assay of mesenteric blood. The rate of absorption of each species was used to calculate apparent permeability (Papp) and subsequently the predicted bioavailability. Results from studies tith oligomers of PEG 400 showed an over prediction of bioavailability v&h a lack of size discrimination and led to the hypoihesis that, under these experimental conditions, the tight junctions become dilated from 5.3A (determined from EM measurements) to 7.3A.(i) This theory was tested under the same experimental conditions v&h the ‘H-D peptide molecules as probes. The bioavailabilitles were again over predicted, v&h the same lack of size discrimination. Correction of these values by reducing the pore size from 7.3A to 5.3A brought the values closer in line tith the expected in tivo values (Table 1). D-Peptide PlteAla PbeVal PheStr PheAlaVal Fobs 29.6 26 6 8.6 28 Fpred 99.9 94.1 63.4 55 2 Fpred con 50.2 11 1 4.95 0.26 Table 1: Observed (Fobs) and predicted (Fpred) oral for ‘H-D paptides and predicted values corrected using size dilation (Fpred corr). (n=5)
PheAlaValAla 11 95.9 4.77 bioavailabilities theofetical pore
Similar experiments have been performed tith in situ perfused ileum using “C-PEG 400 as a probe. The results suggest that jejunum and ileum could have different functional pore sizes. (1) Stretch et al 1997. Eur J Pharm SCI. S(Suppl 2):559.
338
340
SELECTIVE SEROTONINE REUPTAKE INHIBITORS @SRI) AND BREAST-FEEDING - HOW DO WE OBTAIN INFORMATION?
PREDlCTlON OF GASTROINTESTINAL ABSORPTlON PROPERTlES OF LAXATlVES BY THREE-DIMENSIONAL SOLUBILITY PARAMETERS ,!. Rreitkreutz
Ynavild Berasholm, Hedvig Nordeng, lngrid Matheson Department of Pharmacotherapeutics, University of Oslo, P.O.B. 1085 Blindern N-0316 Oslo, Norway. Introduction
The SSRls are a new group of antidepressants with mild and moderate depression as indication. Prior to registration little documentation exists on use during breast-feeding, as women and especially women of childbearing age are rarely included in clinical trials. We are conducting a pharmacokinetic study of two SSRls (paroxetine, citalopram + desmethylcitalopram) in maternal and infant plasma, umbilical cord blood and breast milk in lactating mothers under maintenance therapy. The aim of the study is to estimate the amount and safety of SSRls while breast-feeding. Steady state milk concentrations are measured and the relative doses are calculated. Preliminary results will be presented. Conclualons
Deciding whether to recommend SSRls during breastfeeding-require critical evaluation of a sparse amount of documentation. However, data on fluoxetine transfer is extensive and the drug should not be recommended during breast-feeding.
Institute for Pharmaceutical Technology, Westphalien Wilhelms-University, Corrensstr. 1, 48149 Monster, Germany Recently it was demonstrated that Hansen’s threedimensional solubility parameters can predict absorption properties of drugs in humans. In the present investigations, the solubility parameter concept was proved for poorly absorbed substances which are commercially available as laxatives. The solubility parameters were calculated by the group contribution methods according to Fedors and Van Krevelen with the help of the self-made computer program SPWin. The calculated data was transferred into a Bagley diagram and related to the specific points of well-absorbed drug substances. All laxatives in the present study are located outside the postulated area of optimal absorption with the exception of Bisacodyl which is known to be a well-absorbed prodrug. Its active metabolite can be found close to the points of other gut wall irritating agents. Osmotic active substances exhibit typical locations within the Bagley diagram due to their large partial solubility parameter of hydrogen bond formation ability. The specific points of the water-binding polymers poly(ethylene glycol) and polycarbophil are located near to the area of optimal absorption.
339
331 dttermlnatiottofftw radkal uvengeta by. superoxIdediamtttw blaamaor
In v&m
L. ccmputcll4 G. Pavetn.M.‘IhnuKlti Dcpo#mcntoJChemhy _ Universify ofRome “LaSqLmd’ P.lc Aldo Mom 5 - 00185 Rm (lX4Ll.4)
HYPOTHESIS IN THE VALIDATION OF A DILATION ANAESTHETISED RAT Amanda Malcolm Rowiand Schoolof Pharmacy andPharmacetiical Sciences Unwerstyof Manchester. Ml3 QPL. UK. an extensive program to characterise paracellular As part of absorption, studies have been performed in the in situ perfused rat jejunum tith the aim of predicting in viva oral bioavailability. Absorption of “C-PEG 400 oligomen and ‘H-D peptide probes was assessed from a recirculating isotonic media, over a period of 1 hour by collection and HPLC assay of mesenteric blood. The rate of absorption of each species was used to calculate apparent permeability (Papp) and subsequently the predicted bioavailability. Results from studies tith oligomers of PEG 400 showed an over prediction of bioavailability v&h a lack of size discrimination and led to the hypoihesis that, under these experimental conditions, the tight junctions become dilated from 5.3A (determined from EM measurements) to 7.3A.(i) This theory was tested under the same experimental conditions v&h the ‘H-D peptide molecules as probes. The bioavailabilitles were again over predicted, v&h the same lack of size discrimination. Correction of these values by reducing the pore size from 7.3A to 5.3A brought the values closer in line tith the expected in tivo values (Table 1). D-Peptide PlteAla PbeVal PheStr PheAlaVal Fobs 29.6 26 6 8.6 28 Fpred 99.9 94.1 63.4 55 2 Fpred con 50.2 11 1 4.95 0.26 Table 1: Observed (Fobs) and predicted (Fpred) oral for ‘H-D paptides and predicted values corrected using size dilation (Fpred corr). (n=5)
PheAlaValAla 11 95.9 4.77 bioavailabilities theofetical pore
Similar experiments have been performed tith in situ perfused ileum using “C-PEG 400 as a probe. The results suggest that jejunum and ileum could have different functional pore sizes. (1) Stretch et al 1997. Eur J Pharm SCI. S(Suppl 2):559.
338
340
SELECTIVE SEROTONINE REUPTAKE INHIBITORS @SRI) AND BREAST-FEEDING - HOW DO WE OBTAIN INFORMATION?
PREDlCTlON OF GASTROINTESTINAL ABSORPTlON PROPERTlES OF LAXATlVES BY THREE-DIMENSIONAL SOLUBILITY PARAMETERS ,!. Rreitkreutz
Ynavild Berasholm, Hedvig Nordeng, lngrid Matheson Department of Pharmacotherapeutics, University of Oslo, P.O.B. 1085 Blindern N-0316 Oslo, Norway. Introduction
The SSRls are a new group of antidepressants with mild and moderate depression as indication. Prior to registration little documentation exists on use during breast-feeding, as women and especially women of childbearing age are rarely included in clinical trials. We are conducting a pharmacokinetic study of two SSRls (paroxetine, citalopram + desmethylcitalopram) in maternal and infant plasma, umbilical cord blood and breast milk in lactating mothers under maintenance therapy. The aim of the study is to estimate the amount and safety of SSRls while breast-feeding. Steady state milk concentrations are measured and the relative doses are calculated. Preliminary results will be presented. Conclualons
Deciding whether to recommend SSRls during breastfeeding-require critical evaluation of a sparse amount of documentation. However, data on fluoxetine transfer is extensive and the drug should not be recommended during breast-feeding.
Institute for Pharmaceutical Technology, Westphalien Wilhelms-University, Corrensstr. 1, 48149 Monster, Germany Recently it was demonstrated that Hansen’s threedimensional solubility parameters can predict absorption properties of drugs in humans. In the present investigations, the solubility parameter concept was proved for poorly absorbed substances which are commercially available as laxatives. The solubility parameters were calculated by the group contribution methods according to Fedors and Van Krevelen with the help of the self-made computer program SPWin. The calculated data was transferred into a Bagley diagram and related to the specific points of well-absorbed drug substances. All laxatives in the present study are located outside the postulated area of optimal absorption with the exception of Bisacodyl which is known to be a well-absorbed prodrug. Its active metabolite can be found close to the points of other gut wall irritating agents. Osmotic active substances exhibit typical locations within the Bagley diagram due to their large partial solubility parameter of hydrogen bond formation ability. The specific points of the water-binding polymers poly(ethylene glycol) and polycarbophil are located near to the area of optimal absorption.