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Absorption Enhancement of Rectally Infused Cefoxitin by Medium Chain Monoglycerides in Conscious Rats
Absorption Enhancement of Rectally Infused Cefoxitin by Medium Chain Monoglycerides in Conscious Rats YOSHITERU WATANABE**, EWOUD J. AND DOLJWE D. BREIMER*
VAN
HOOGDALEM*', ALBERTUSG.DE BOER*,
Received March 7,1988, from the "Center for Bio-PharmaceuticalSciences,. Division of Pharmacology, Sylvius Labs., Leiden University, *Visiting scientist from: Showa College of Accepted for publication May 24, 1988. P.O. Box 9503, 2300 RA Leiden, The Netherlands. Pharmaceutical Sciences, Department of Pharmaceutics, Setagaya-ku,Tokyo 154, Japan. Abstract 0 The enhancing effect of the medium chain monoglycerides glycer-yl-1-rnonooctanoate (GMO), glyceryl-1-rnonodecanoate (GMD), and glyceryl-1-monododecanoate (GMDD) on rectal absorption of the cephalosporin antibiotic cefoxitin [(6R,7S)9-hydroxymethyl)-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamido]-5-thia-l-azabicyclo[4.2.0]oct-2ene-2-carboxylicacid carbamate (ester)] was investigatedin unanesthetized rats. Rectal infusion of 3 mg of cefoxitin sodium without monoglyceride resulted in a mean bioavailability of 31 rt 18% and a mean residence time (MRT) of 134 -+ 44 min. Coadministration with 53% (w/w) GMO significantly enhanced cefoxitin absorption, resulting in a mean bioavailabilityof 84 ? 11% and a mean MRT of 75 r 8 min. In a lower concentration, GMD (13% w/w) also significantly promoted cefoxitin bioavailabilityto 68 2 14% and reduced MRT to 70 11 min. With GMDD only, a trend of increasing bioavailability with increasing monoglyceride concentration was observed, which may be explained by its limited aqueous solubility. Concerningthe action of GMO and GMD, the longer monoglyceride is, in terms of effectiveconcentration,more potent in enhancing the extent and rate of cefoxitin absorption. However, a further increase in chain length results in a loss of effect, indicating that the effect of monoglycerideson drug absorption may be determined by their intrinsic absorption enhancing action and solubility.
*
The poor bioavailability o f many polar drugs o n oral or rectal delivery l i m i t s t h e i r applicability t o injection therapy. The effect o f coadministration w i t h compounds l i k e mixed micelles,' enamines,2 NSAIDS,~ b i l e salts,4 EDTA,6 and fatty acid derivativesa o n t h e rectal absorption of poorly absorbed drugs has been the subject o f several studies. The medium chain glyceride m i x t u r e MGK (a commerciall y available preparation containing glyceryl monoctanoate, glyceryl dioctanoate, glyceryl trioctanoate, glycerol, and octanoic acid) was shown t o effectively enhance the rectal uptake o f the poorly absorbed antibiotic cefmetazole in rabbits7 and ratss, the effect being dependent o n delivery rate.9 The absorption enhancing properties of MGK and the reported low oral and rectal toxicity of this preparationlo suggest MGK to be an interesting absorption enhancing agent, o f which the monoglyceride component seems t o be one of the parameters determining the effect of this preparation o n drug absorption.8J1 The aim o f the present study was t o evaluate the enhancing effect of the separate medium chain monoglycerides
glyceryl-1-monooctanoate, glyceryl-1-monodecanoate,and glyceryl-1-monododecanoateo n the rectal absorption o f the cephalosporin antibiotic cefoxitin in unanesthetized rats.
Experimental Section
zol-2-yl)thio]methyl]-8-oxo-7-[2-~l~-tetrazol-l-yl~acetamido~5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylatel were obtained as gifts from Merck, Sharp & Dohme (Haarlem, The Netherlands) and Eli Lilly Nederland (Utrecht, The Netherlands), respectively. Glyceryl-1-monooctanoate (GMO) was a gift from Tramedico (Weesp, The Netherlands). Glyceryl-1-monodecanoate (GMD) and glyceryl-lmonododecanoate (GMDD) were purchased from Sigma Chemical Company (St. Louis, MO). Polyethylene glycol 400 (PEG) was obtained from Brocacef bv (Maarssen, The Netherlands). All reagents used were of analytical grade. Polyvinylchloride and Teflon cannulas were supplied by Talas (Ommen, The Netherlands). The pump used for drug delivery was manufactured by B. Braun (Melsungen, F.R.G.). Drug Preparations-For iv infusion, a solution containing cefoxitin sodium (15mg/mW was used (made isotonic by adding NaC1). For rectal infusion, preparations were used containing cefoxitin sodium (15 mg/mL), PEG (10% w/w), and GMO, GMD, or GMDD, in concentrations of 0-75% (wiw). Polyethylene glycol was added to lower the viscosity of the preparations in order to enable administration through the delivery device that was inserted rectally. For studying the interaction of rectally delivered monoglycerides with the elimination kinetics of cefoxitin, preparations containing PEG (10% w/w) and GMO (53%w/w) or GMD (13% w/w) were used. Animal Experiments-Animals-Male Wistar rats of laboratory breed (175-210 g) were fasted for 16 h prior to the experiments. They were allowed free access to water. Drug Delivery and Blood Sampling-Drug delivery and blood sampling were performed as described previously.12 Preparations were delivered iv or rectally as a linear infusion of 200 pL over a 32min period. Blood samples of 100 pL were taken from a cannulated carotid artery at regular intervals after starting the experiment. Assay of Cefoxitin-After extraction of the hemolyzed blood samples, cefoxitin was assayed by reversed-phase HPLC as described previously.'* Cefazolin sodium was used as the internal standard. Data Analysis-The area under the individual cefoxitin blood concentration-time curves to the last sampling point was calculated from t = 0 to maximal concentration with the linear trapezoidal rule and, after the maximal concentration to the last sampling point, with the logarithmic trapezoidal rule.'3 Because of an irregular pattern of the apparent elimination phase, a reliable value of the elimination rate constant could not be determined for some of the curves. For this reason, the total area under the curve (AUC) was calculated by extrapolation to infinity using the elimination rate constant observed after iv infusion. Bioavailability (F)was calculatx loo%, where the subscripts rectal and iv ed as (AUC,,,,/AUCiJ refer to rectal and iv infusion, respectively. The mean residence time (MRT) was determined by statistical moments the0ry.l' Because all deliveries were performed by infusion over a 32-min period, MRT values were not corrected for delivery rate. Systemic clearance of cefoxitin was calculated as DIAUC, where D is the dose of iv infused cefoxitin sodium. For statistical analysis of the results, the Wilcoxon rank sum test was used, maintaining a comparisonwise error rate of 0.05.
M a t e r i a l d e f o x i t i n sodium [Mefoxin; sodium (6R,7S)-3-(hydroxResults ymethyl)-7-meth0xy-8-oxo-7-[2-(2-thienyl)acetamidol-5-thiaRectal infusion o f cefoxitin sodium without monoglyceride l-aza-bicyclo[4.2.01oct-2-ene-2-carboxylate carbamate(ester)l and cefazolin sodium [Kefzol; sodium (6R,7R)-3-[[(5-methyl-1,3,4-thiadia- resulted in l o w mean blood concentrations of cefoxitin, which OO22-3%9/88/1OoO-0847$0l.OC/O 0 1988, American PharmaceuticalAssociation
Journal of PharmaceuticalSciences / 847 Vol. 77, No. 10, October 1988
were considerably increased by coadministration with 53% (w/w)GMO or 13%(w/w) GMD (Figure 1). Increasing concentrations of GMO or GMD resulted in increasing AUC values of cefoxitin, although interanimal variability proved to be considerable (Figure 2). A statistically significant effect of GMO was reached a t a concentration of 53% w/w (Figure 2)
50
100
and of GMD a t a lower concentration (13% w/w; Figure 2). The latter AUC value was significantly lower than that reached with 53% (w/w) GMO. Using GMDD only, a trend of increasing AUC values with increasing concentration was observed (Figure 2). The effect of higher concentrations of GMD and GMDD could not be evaluated because of their limited solubility. Regarding the effects on absorption rate, coadministration of cefoxitin with 26%(w/w) and 53%(w/w)GMO significantly reduced MRT (Figure 3). With GMD this occurred at lower concentrations (7 and 13% w/w), whereas GMDD did not reduce the MRT of cefoxitin (Figure 3). Concurrent rectal infusion of 53%(w/w)GMO or 13%(w/w) GMD during iv infusion of cefoxitin sodium resulted in mean ( S D ) systemic clearance values of cefoxitin of 7.3 5 2.1 (n = 6) and 8.2 +- 0.4 mumin (n = 3), respectively. These values are in good agreement with the value of 7.1 & 1.1 mumin (n = 6) obtained without concurrent rectal monoglyceride delivery. This excludes an interaction of rectally delivered monoglycerides with cefoxitin elimination kinetics.
Discussion
200
150
Time (min)
Figure 1-Mean cefoxitin blood concentrations (? SD)during and after rectal infusion over a period of 32 min of 200 pl of a solution containing 3 mg of cefoxitin sodium in polyethylene glycol 400 (10% w/w) without monoglyceride (0,n = 6), with 53% (w/w) GMO (A,n = 6), and with 13% (w/w) GMD (0,n = 6).
The extent of rectal cefoxitin absorption proved to be enhanced by the medium chain monoglycerides GMO and GMD, the longer monoglyceride being more potent in terms of effective concentration (Figure 2). However, stronger effects on cefoxitin bioavailabilities were obtained with GMO compared with the longer monoglycerides, the applicability of which was restricted by their limited solubility. This indicates that the effect of monoglycerideson drug absorption is determined by both the intrinsic absorption promoting effect and hydrophilic properties. Interestingly, GMO and GMD exert a statistically significant effect on absorption rate at lower concentrations compared with the effect on extent of absorption (Figures 2 and 3). This suggests that the lower concentrations of GMO and GMD induce an enhancing effect on the rate of cefoxitin absorption, resulting in a significantly reduced MRT.As the extent of absorption is not significantly enhanced at these concentrations, this effect appears to be quickly reversible. The curve describing the relation between GMO concentration and effect on MRT shows an optimal effect at 26% w/w 1501
I
b
‘P
01s
i
I
5
,
10
I
50
1
100
concentration monoglyceride (%)
Figure 2-Mean AUC&,,,, values (?SO) of cefoxitin sodium versus the concentration of GMO (O), GMD (A),and GMDD (V) obtained after rectal infusion of 3 mg of cefoxitin sodium in polyethylene glycol 400 (10% w/w) with different concentrations of monoglycerides; represents the mean value after iv infusion (n = 6). Symbols represent the means of 3-6 rats, and statistical comparison was performed using the data of rectal infusion without monoglyceride (n = 6) as the control. Groups containing at least six animals were tested [viz., GMD (7 and 13% w/w) and GMO (7, 13, 26, and 53% w/w)], and 53% (w/w) GMO was compared with 13% (w/w) GMD. Key: significantly different from delivery without monoglyceride; (**) significantly different from delivery with 13% (w/w) GMD (p < 0.05, Wilcoxon rank sum test).
r)
848 / Journal of Pharmaceutical Sciences Vol. 77, No. 10, October 1988
‘
r/l
0
I
5 10 50 Concentration monoglyceride ( % I
0.5
1
100
Figure 3-Mean MRT values (?SO) of cefoxitin sodium versus concentration of monoglyceride observed after rectal infusion of 3 mg of cefoxitin sodium in polyethylene glycol 400 (10% w/w) with different concentrationsof monoglycerides;symbols and statistics as in Figure 2.
(Figure 31, indicating that GMO concentrations >26% (w/w) hinder cefoxitin from reaching the absorption site, resulting in an increase of MRT. Therefore, it is conceivable that at concentrations of monoglyceride exceeding those in this study, the absorption rate will be retarded to such an extent that the amount absorbed will also decrease. Probably this mechanism explains the observations of Sekine et al. who described a lowering of intestinal cefmetazole bioavailability in rats when the amount of monoglyceride was increased from 55%to >80%, and when GMO was replaced by the less soluble monoglyceride GMD.lS Concerning the mechanism of action of medium chain monoglycerides, a n effect on the transcellular absorption pathway may be involved, as has been described in the case of glycerylmonooleate. This monoglyceride has been shown to destabilize membrane structure, resulting in enhanced membrane permeability.16 It is conceivable that an additional membrane permeability effect may be caused by extraction of cholesterol out of the epithelial membrane, since GMO has been reported to solubilize cholester01.~7 This study demonstrates that medium chain monoglycerides can be used as effective rectal absorption enhancers. The applicability of fatty acid derivatives as absorption promoters requires further studies.
4. Murakami, T.; Sasaki, Y.; Yamajo, R.; Yata, N. Chem. Pharrn. Bull. 1984,32, 1948-1955. 5. Nishihata, T.; Lee, C-S.; Rytting, J. H.; Higuchi, T. J. Pharm. Phurmacol. 1987.39, 180-184. 6. Nishimura, K.; Nozaki, Y.; Yoshimi, A.; Nakamura, S.; Kitagawa, M.; Kakeya, N.; Kaito, K.Chem. Pharm. Bull. 1985,33, 2 91.. -8 -2 --2__ 7. Sekine, M.; Sasahara, K.; Kojima, T.; Hasegawa, K.; Okada, R. Chem. Pharm. Bull. 1984,33,4189-4192. 8. Sekine, M.; Sasahara, K.; Kojima, T.; Hasegawa, K.; Okada, R. Awazu, S.J. Pharmacobio-Dyn. 1984, 7,856-863. 9. Van Hoo dalem, E. J.; Stijnen, A. M.; De Boer, A. G.; Breimer, D. D. J.h a r m . P h u r m o l . 1988,40,329-332. 10. Sekine, M.; Maeda, E.;Sasahara, K.; Okada, R.; Kimura, K.; Fukami, M.; Awazu, S. J.Pharmacobi+Dyn. 1985,8,633-644. 11. Hi aki, K.; Kishimoto, I.; Komatsu, H.; Hashida, M.; Sezaki, H. J . f ’ h u r m o b k D y n . 1986,9,532-539. 12. Van Hoo dalem, E. J.; Van Kan, H. J. M.; De Boer, A. G.; Breimer, D. J. Controlled Release 1988, 7,53-60. 13. Chiou, W. L. J. Pharmokinet. Bwpharm. 1978,6,539-546. 14. Gibaldi, M.; Perrier, D. Phurmokinetics, 2nd ed.; Marcel Dekker: New York, 1982; pp 409-417. 15. Sekine, M.;Terashima, H.; Sasahara, K.; Nishimura, K.; Okada, R.; Awazu, S. J.Pharmobio-Dyn. 1985,8,286-295. 16. Muranushi, N.; Takagi, N.; Muranishi, S.; Sezaki, H. Chem. Phys. Lipids 1981,28,269-279. 17. Lillemoe, K. D.; Gadacz, T. R.; Harmon, J. W. Surg. Gynecol. Obstet. 1982,155,13-16.
%.
References and Notes 1.
Fukui,H.; Murakami, M.; Yoshikawa, H.; Takada, K.; Murani-
shi. S. J.Pharmobio-Dyn. 1987,10,236-242. 2. Miyake, M.; Nishihata, T.; Wada, N.; Takeshima, E.; Kamada, A. Chem. Pharm. Bull. 1984,32,2020-2025. 3. Nakanishi, K.; Masada, M.; Nadai, T. Chem.Pharm. Bull. 1986, 34,2628-2631.
Acknowledgments The authors wish to thank Tramedico (Wees , The Netherlands), Merck, Sh & Dohme (Haarlem, The NetheJands), and Eli Lilly Nederlandqtrecht, The Netherlands) for kindly supplying GMO, cefoxitin sodium, and cefazolin sodlum, respectively.
Journal of Pharmaceutical Sciences / 849 Vol. 77, No. 10, October 1988
VAN
HOOGDALEM*', ALBERTUSG.DE BOER*,
Received March 7,1988, from the "Center for Bio-PharmaceuticalSciences,. Division of Pharmacology, Sylvius Labs., Leiden University, *Visiting scientist from: Showa College of Accepted for publication May 24, 1988. P.O. Box 9503, 2300 RA Leiden, The Netherlands. Pharmaceutical Sciences, Department of Pharmaceutics, Setagaya-ku,Tokyo 154, Japan. Abstract 0 The enhancing effect of the medium chain monoglycerides glycer-yl-1-rnonooctanoate (GMO), glyceryl-1-rnonodecanoate (GMD), and glyceryl-1-monododecanoate (GMDD) on rectal absorption of the cephalosporin antibiotic cefoxitin [(6R,7S)9-hydroxymethyl)-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamido]-5-thia-l-azabicyclo[4.2.0]oct-2ene-2-carboxylicacid carbamate (ester)] was investigatedin unanesthetized rats. Rectal infusion of 3 mg of cefoxitin sodium without monoglyceride resulted in a mean bioavailability of 31 rt 18% and a mean residence time (MRT) of 134 -+ 44 min. Coadministration with 53% (w/w) GMO significantly enhanced cefoxitin absorption, resulting in a mean bioavailabilityof 84 ? 11% and a mean MRT of 75 r 8 min. In a lower concentration, GMD (13% w/w) also significantly promoted cefoxitin bioavailabilityto 68 2 14% and reduced MRT to 70 11 min. With GMDD only, a trend of increasing bioavailability with increasing monoglyceride concentration was observed, which may be explained by its limited aqueous solubility. Concerningthe action of GMO and GMD, the longer monoglyceride is, in terms of effectiveconcentration,more potent in enhancing the extent and rate of cefoxitin absorption. However, a further increase in chain length results in a loss of effect, indicating that the effect of monoglycerideson drug absorption may be determined by their intrinsic absorption enhancing action and solubility.
*
The poor bioavailability o f many polar drugs o n oral or rectal delivery l i m i t s t h e i r applicability t o injection therapy. The effect o f coadministration w i t h compounds l i k e mixed micelles,' enamines,2 NSAIDS,~ b i l e salts,4 EDTA,6 and fatty acid derivativesa o n t h e rectal absorption of poorly absorbed drugs has been the subject o f several studies. The medium chain glyceride m i x t u r e MGK (a commerciall y available preparation containing glyceryl monoctanoate, glyceryl dioctanoate, glyceryl trioctanoate, glycerol, and octanoic acid) was shown t o effectively enhance the rectal uptake o f the poorly absorbed antibiotic cefmetazole in rabbits7 and ratss, the effect being dependent o n delivery rate.9 The absorption enhancing properties of MGK and the reported low oral and rectal toxicity of this preparationlo suggest MGK to be an interesting absorption enhancing agent, o f which the monoglyceride component seems t o be one of the parameters determining the effect of this preparation o n drug absorption.8J1 The aim o f the present study was t o evaluate the enhancing effect of the separate medium chain monoglycerides
glyceryl-1-monooctanoate, glyceryl-1-monodecanoate,and glyceryl-1-monododecanoateo n the rectal absorption o f the cephalosporin antibiotic cefoxitin in unanesthetized rats.
Experimental Section
zol-2-yl)thio]methyl]-8-oxo-7-[2-~l~-tetrazol-l-yl~acetamido~5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylatel were obtained as gifts from Merck, Sharp & Dohme (Haarlem, The Netherlands) and Eli Lilly Nederland (Utrecht, The Netherlands), respectively. Glyceryl-1-monooctanoate (GMO) was a gift from Tramedico (Weesp, The Netherlands). Glyceryl-1-monodecanoate (GMD) and glyceryl-lmonododecanoate (GMDD) were purchased from Sigma Chemical Company (St. Louis, MO). Polyethylene glycol 400 (PEG) was obtained from Brocacef bv (Maarssen, The Netherlands). All reagents used were of analytical grade. Polyvinylchloride and Teflon cannulas were supplied by Talas (Ommen, The Netherlands). The pump used for drug delivery was manufactured by B. Braun (Melsungen, F.R.G.). Drug Preparations-For iv infusion, a solution containing cefoxitin sodium (15mg/mW was used (made isotonic by adding NaC1). For rectal infusion, preparations were used containing cefoxitin sodium (15 mg/mL), PEG (10% w/w), and GMO, GMD, or GMDD, in concentrations of 0-75% (wiw). Polyethylene glycol was added to lower the viscosity of the preparations in order to enable administration through the delivery device that was inserted rectally. For studying the interaction of rectally delivered monoglycerides with the elimination kinetics of cefoxitin, preparations containing PEG (10% w/w) and GMO (53%w/w) or GMD (13% w/w) were used. Animal Experiments-Animals-Male Wistar rats of laboratory breed (175-210 g) were fasted for 16 h prior to the experiments. They were allowed free access to water. Drug Delivery and Blood Sampling-Drug delivery and blood sampling were performed as described previously.12 Preparations were delivered iv or rectally as a linear infusion of 200 pL over a 32min period. Blood samples of 100 pL were taken from a cannulated carotid artery at regular intervals after starting the experiment. Assay of Cefoxitin-After extraction of the hemolyzed blood samples, cefoxitin was assayed by reversed-phase HPLC as described previously.'* Cefazolin sodium was used as the internal standard. Data Analysis-The area under the individual cefoxitin blood concentration-time curves to the last sampling point was calculated from t = 0 to maximal concentration with the linear trapezoidal rule and, after the maximal concentration to the last sampling point, with the logarithmic trapezoidal rule.'3 Because of an irregular pattern of the apparent elimination phase, a reliable value of the elimination rate constant could not be determined for some of the curves. For this reason, the total area under the curve (AUC) was calculated by extrapolation to infinity using the elimination rate constant observed after iv infusion. Bioavailability (F)was calculatx loo%, where the subscripts rectal and iv ed as (AUC,,,,/AUCiJ refer to rectal and iv infusion, respectively. The mean residence time (MRT) was determined by statistical moments the0ry.l' Because all deliveries were performed by infusion over a 32-min period, MRT values were not corrected for delivery rate. Systemic clearance of cefoxitin was calculated as DIAUC, where D is the dose of iv infused cefoxitin sodium. For statistical analysis of the results, the Wilcoxon rank sum test was used, maintaining a comparisonwise error rate of 0.05.
M a t e r i a l d e f o x i t i n sodium [Mefoxin; sodium (6R,7S)-3-(hydroxResults ymethyl)-7-meth0xy-8-oxo-7-[2-(2-thienyl)acetamidol-5-thiaRectal infusion o f cefoxitin sodium without monoglyceride l-aza-bicyclo[4.2.01oct-2-ene-2-carboxylate carbamate(ester)l and cefazolin sodium [Kefzol; sodium (6R,7R)-3-[[(5-methyl-1,3,4-thiadia- resulted in l o w mean blood concentrations of cefoxitin, which OO22-3%9/88/1OoO-0847$0l.OC/O 0 1988, American PharmaceuticalAssociation
Journal of PharmaceuticalSciences / 847 Vol. 77, No. 10, October 1988
were considerably increased by coadministration with 53% (w/w)GMO or 13%(w/w) GMD (Figure 1). Increasing concentrations of GMO or GMD resulted in increasing AUC values of cefoxitin, although interanimal variability proved to be considerable (Figure 2). A statistically significant effect of GMO was reached a t a concentration of 53% w/w (Figure 2)
50
100
and of GMD a t a lower concentration (13% w/w; Figure 2). The latter AUC value was significantly lower than that reached with 53% (w/w) GMO. Using GMDD only, a trend of increasing AUC values with increasing concentration was observed (Figure 2). The effect of higher concentrations of GMD and GMDD could not be evaluated because of their limited solubility. Regarding the effects on absorption rate, coadministration of cefoxitin with 26%(w/w) and 53%(w/w)GMO significantly reduced MRT (Figure 3). With GMD this occurred at lower concentrations (7 and 13% w/w), whereas GMDD did not reduce the MRT of cefoxitin (Figure 3). Concurrent rectal infusion of 53%(w/w)GMO or 13%(w/w) GMD during iv infusion of cefoxitin sodium resulted in mean ( S D ) systemic clearance values of cefoxitin of 7.3 5 2.1 (n = 6) and 8.2 +- 0.4 mumin (n = 3), respectively. These values are in good agreement with the value of 7.1 & 1.1 mumin (n = 6) obtained without concurrent rectal monoglyceride delivery. This excludes an interaction of rectally delivered monoglycerides with cefoxitin elimination kinetics.
Discussion
200
150
Time (min)
Figure 1-Mean cefoxitin blood concentrations (? SD)during and after rectal infusion over a period of 32 min of 200 pl of a solution containing 3 mg of cefoxitin sodium in polyethylene glycol 400 (10% w/w) without monoglyceride (0,n = 6), with 53% (w/w) GMO (A,n = 6), and with 13% (w/w) GMD (0,n = 6).
The extent of rectal cefoxitin absorption proved to be enhanced by the medium chain monoglycerides GMO and GMD, the longer monoglyceride being more potent in terms of effective concentration (Figure 2). However, stronger effects on cefoxitin bioavailabilities were obtained with GMO compared with the longer monoglycerides, the applicability of which was restricted by their limited solubility. This indicates that the effect of monoglycerideson drug absorption is determined by both the intrinsic absorption promoting effect and hydrophilic properties. Interestingly, GMO and GMD exert a statistically significant effect on absorption rate at lower concentrations compared with the effect on extent of absorption (Figures 2 and 3). This suggests that the lower concentrations of GMO and GMD induce an enhancing effect on the rate of cefoxitin absorption, resulting in a significantly reduced MRT.As the extent of absorption is not significantly enhanced at these concentrations, this effect appears to be quickly reversible. The curve describing the relation between GMO concentration and effect on MRT shows an optimal effect at 26% w/w 1501
I
b
‘P
01s
i
I
5
,
10
I
50
1
100
concentration monoglyceride (%)
Figure 2-Mean AUC&,,,, values (?SO) of cefoxitin sodium versus the concentration of GMO (O), GMD (A),and GMDD (V) obtained after rectal infusion of 3 mg of cefoxitin sodium in polyethylene glycol 400 (10% w/w) with different concentrations of monoglycerides; represents the mean value after iv infusion (n = 6). Symbols represent the means of 3-6 rats, and statistical comparison was performed using the data of rectal infusion without monoglyceride (n = 6) as the control. Groups containing at least six animals were tested [viz., GMD (7 and 13% w/w) and GMO (7, 13, 26, and 53% w/w)], and 53% (w/w) GMO was compared with 13% (w/w) GMD. Key: significantly different from delivery without monoglyceride; (**) significantly different from delivery with 13% (w/w) GMD (p < 0.05, Wilcoxon rank sum test).
r)
848 / Journal of Pharmaceutical Sciences Vol. 77, No. 10, October 1988
‘
r/l
0
I
5 10 50 Concentration monoglyceride ( % I
0.5
1
100
Figure 3-Mean MRT values (?SO) of cefoxitin sodium versus concentration of monoglyceride observed after rectal infusion of 3 mg of cefoxitin sodium in polyethylene glycol 400 (10% w/w) with different concentrationsof monoglycerides;symbols and statistics as in Figure 2.
(Figure 31, indicating that GMO concentrations >26% (w/w) hinder cefoxitin from reaching the absorption site, resulting in an increase of MRT. Therefore, it is conceivable that at concentrations of monoglyceride exceeding those in this study, the absorption rate will be retarded to such an extent that the amount absorbed will also decrease. Probably this mechanism explains the observations of Sekine et al. who described a lowering of intestinal cefmetazole bioavailability in rats when the amount of monoglyceride was increased from 55%to >80%, and when GMO was replaced by the less soluble monoglyceride GMD.lS Concerning the mechanism of action of medium chain monoglycerides, a n effect on the transcellular absorption pathway may be involved, as has been described in the case of glycerylmonooleate. This monoglyceride has been shown to destabilize membrane structure, resulting in enhanced membrane permeability.16 It is conceivable that an additional membrane permeability effect may be caused by extraction of cholesterol out of the epithelial membrane, since GMO has been reported to solubilize cholester01.~7 This study demonstrates that medium chain monoglycerides can be used as effective rectal absorption enhancers. The applicability of fatty acid derivatives as absorption promoters requires further studies.
4. Murakami, T.; Sasaki, Y.; Yamajo, R.; Yata, N. Chem. Pharrn. Bull. 1984,32, 1948-1955. 5. Nishihata, T.; Lee, C-S.; Rytting, J. H.; Higuchi, T. J. Pharm. Phurmacol. 1987.39, 180-184. 6. Nishimura, K.; Nozaki, Y.; Yoshimi, A.; Nakamura, S.; Kitagawa, M.; Kakeya, N.; Kaito, K.Chem. Pharm. Bull. 1985,33, 2 91.. -8 -2 --2__ 7. Sekine, M.; Sasahara, K.; Kojima, T.; Hasegawa, K.; Okada, R. Chem. Pharm. Bull. 1984,33,4189-4192. 8. Sekine, M.; Sasahara, K.; Kojima, T.; Hasegawa, K.; Okada, R. Awazu, S.J. Pharmacobio-Dyn. 1984, 7,856-863. 9. Van Hoo dalem, E. J.; Stijnen, A. M.; De Boer, A. G.; Breimer, D. D. J.h a r m . P h u r m o l . 1988,40,329-332. 10. Sekine, M.; Maeda, E.;Sasahara, K.; Okada, R.; Kimura, K.; Fukami, M.; Awazu, S. J.Pharmacobi+Dyn. 1985,8,633-644. 11. Hi aki, K.; Kishimoto, I.; Komatsu, H.; Hashida, M.; Sezaki, H. J . f ’ h u r m o b k D y n . 1986,9,532-539. 12. Van Hoo dalem, E. J.; Van Kan, H. J. M.; De Boer, A. G.; Breimer, D. J. Controlled Release 1988, 7,53-60. 13. Chiou, W. L. J. Pharmokinet. Bwpharm. 1978,6,539-546. 14. Gibaldi, M.; Perrier, D. Phurmokinetics, 2nd ed.; Marcel Dekker: New York, 1982; pp 409-417. 15. Sekine, M.;Terashima, H.; Sasahara, K.; Nishimura, K.; Okada, R.; Awazu, S. J.Pharmobio-Dyn. 1985,8,286-295. 16. Muranushi, N.; Takagi, N.; Muranishi, S.; Sezaki, H. Chem. Phys. Lipids 1981,28,269-279. 17. Lillemoe, K. D.; Gadacz, T. R.; Harmon, J. W. Surg. Gynecol. Obstet. 1982,155,13-16.
%.
References and Notes 1.
Fukui,H.; Murakami, M.; Yoshikawa, H.; Takada, K.; Murani-
shi. S. J.Pharmobio-Dyn. 1987,10,236-242. 2. Miyake, M.; Nishihata, T.; Wada, N.; Takeshima, E.; Kamada, A. Chem. Pharm. Bull. 1984,32,2020-2025. 3. Nakanishi, K.; Masada, M.; Nadai, T. Chem.Pharm. Bull. 1986, 34,2628-2631.
Acknowledgments The authors wish to thank Tramedico (Wees , The Netherlands), Merck, Sh & Dohme (Haarlem, The NetheJands), and Eli Lilly Nederlandqtrecht, The Netherlands) for kindly supplying GMO, cefoxitin sodium, and cefazolin sodlum, respectively.
Journal of Pharmaceutical Sciences / 849 Vol. 77, No. 10, October 1988