Eur J Clin Pharmacol (1991) 40:383-386
Eorop.a0Joorof 0a,
003169709100094I
@Springer-Verlag 1991
Differential effects of sodium bicarbonate and aluminium hydroxide on the absorption and activity of glipizide K. T. Kivistii and P. J. Neuvonen Department of Pharmacology,University of Turku, Turku, Finland Received: July 5, 1990/Accepted: October 4, 1990
Summary. The effects of sodium bicarbonate and aluminium hydroxide on the absorption and activity of glipizide have been studied in healthy volunteers in two randomized cross-over trials. After an overnight fast, 5 mg glipizide was given either with 150 ml water or with water containing 3.0 g sodium bicarbonate or 1.0 g aluminium hydroxide. Sodium bicarbonate significantly increased the A U C of plasma glipizide from 0 to 0.5 h, 0 to I h, and from 0 to 2 h (six-, four- and twofold, respectively). The time to peak concentration (tm~) fell from 2.5 h during the control phase to 1.0 h during the sodium bicarbonate phase. The absorption half-life (tma), lag time and mean residence time (MRT) were also significantly decreased. No significant change in peak plasma concentration (Cmax), total A U C or elimination half-life (tl/2) was noted. The decremental plasma glucose areas from 0 to i h and 0 to 2 h were significantly larger (80% and 50%, respectively) than during the control phase. The maximal decrease in glucose was 50% greater during the sodium bicarbonate phase, and the time to reach it was reduced by 35 rain. Aluminium hydroxide had no significant effects on the rate or extent of absorption of glipizide, and the glucose response also remained unaffected. It is concluded that the concomitant ingestion of sodium bicarbonate and glipizide may result in accelerated absorption of glipizide and an increased effect on glucose. A common dose of aluminium hydroxide did not appear to affect the absorption of glipizide. Key words: Glipizide, gastrointestinal absorption, sodium bicarbonate, aluminium hydroxide, glucose, drug interaction, healthy volunteers
Glipizide is absorbed completely and relatively rapidly, even though it is only sparingly soluble in the acidic gastric contents [1]. However, absorption of glipizide and other sulphonylure as may b e unusually slow in some healthy subjects, as well as in certain diabetic patients [2-4]. It is often recommended that sulphonylureas be taken 30 min before meals to ensure their rapid absorption [5]. For example,
food can delay the absorption of glipizide, and taking glipizide on an empty stomach has been shown to result in better disposition of glucose in diabetic patients [6]. Antacids affect the absorption of many drugs, and clinically important interactions have been described [7, 8]. The consequences of drug-antacid interactions are very dependent on the antacid used, but reduced absorption of the affected drug is most often encountered. Magnesium hydroxide and sodium bicarbonate may increase the rate of absorption of certain weakly acidic drugs, e.g. tolfenamic and mefenamic acids [9], and naproxen [10], respectively. On the other hand, aluminium hydroxide, alone or in combination with other antacids, typically reduces or delays drug absorption [10-12]. Recently, magnesium hydroxide was shown to accelerate the absorption and increase the glucose-lowering effect of glipizide (Kivist6 and Neuvonen, unpublished observations). There do not appear to be other published data about the possible effects of different antacids on the absorption of sulphonylureas. It was considered important to determine whether additional interactions could occur between these two widely used drug groups. In the present study, the effects of sodium bicarbonate and aluminium hydroxide on the gastrointestinal absorption and glucose response of glipizide have been studied in healthy volunteers.
Materials and methods
General design The present investigation comprised two separate studies. Six healthy volunteers participated in the first study and 7 in the second. All volunteers were considered healthy on the basis of medical history, physical examination, and routine laboratory tests (renal and hepatic function, fasting glucose, haemoglobin). The subjects were thoroughly informed, both verbally and in writing, and informed consent was obtained. The study protocol was accepted by the local Ethics Committee. A randomized cross-overdesign was employed, with two phases, at least one week apart. The test drugs were ingested after an over-
384
K. T. Kivist6 and E J. Neuvonen: Absorption and effect of glipizide
night fast together with 150 ml water or with 150 ml water containing the antacid studied. The subjects were kept supine, under direct medical supervision, for 2 h from the beginning of the study. No food was allowed during that time; breakfast was given after the 2 h blood sample, and then the subjects were allowed to move and eat as desired. Hypoglycaemic symptoms were monitored on the study days. Glucose both for oral and intravenous administration was available in case of severe hypoglycaemia. It was not needed. Timed venous blood samples from an indwelling catheter were collected in heparinized tubes 0,15,22, 30 and 45 min, and 1,1.5, 2, 3, 4, 5, 7 and 10 h after drug ingestion. The tubes were chilled on ice both before and after sample collection. Plasma was separated within 30 rain at + 4 °C, and the samples were stored at - 20 °C until analysed.
Effect of sodium bicarbonate on glipizide absorption One man and 5 women with a mean (SEM) age of 23 (0.8) y, and a mean body weight of 59 (2.8) kg, ingested 5 mg glipizide (Melizid, Medica, Finland) either with 150 ml water, or with 150 ml water containing 3.0 g sodium bicarbonate (NaHCO3; E.Merck, Darmstadt, West-Germany).
Effect of aluminium hydroxide on glipizide absorption Two men and 5 women with a mean (SEM) age of 23 (0.7) y, and a mean body weight of 61 (3.7) kg, ingested 5 mg glipizide (Melizid, Medica, Finland) either with 150 ml water, or with 150 ml water containing 1.0 g aluminium hydroxide (AI(OH)3; E. Merck, Darmstadt, West-Germany).
Analytical methods Plasma glipizide concentrations were determined by reversed phase HPLC, using a modified version of two previously published methods [13, 14]. To i ml plasma, 0.5 M HC1 0.2 ml and 400 ng tolbutamide, the internal standard, were added. The sample was then extracted with 5 ml of a 1 : 1 mixture of dichloromethane and hexane and shaken for 4 min. After centrifugation, the organic phase was evaporated to dryness under a stream of nitrogen at 40 °C. The residue was redissolved in 70 gl mobile phase, and a 20 ~tl aliquot was injected into the chromatograph. The mobile phase consisted of a mixture of methanol and 0.01 M phosphate buffer at pH 3.5 (55 : 45). The flow-rate was 1.2 ml. min- t. The UV detector was set at 229 nm, and the sensitivity was kept at 0.02 a. u. f. s. The inter-assay coefficient of variation was 4.4% (mean 218 ng-ml t, n = 8).
Plasma glucose concentrations up to the breakfast time (2 h) were determined by the glucose oxidase method (Reflotron, Boehringer Mannheim GmbH, West-Germany). The inter-assay coefficient of variation was 3.3% (mean 5.6 mmol. 1 1, n = 8).
Pharmacokinetic analysis The plasma concentration-time data for glipizide were fitted to an open one- or two-compartment model, whichever gave the better fit, by weighted least squares analysis, using the SIPHAR pharmacokinetic curve fitting programme (SIMED, Creteil, France). The absorption of glipizide was characterized by the peak time (tmax), halflife of absorption (tl/2a), lag time, peak plasma concentration ( C m a x ) , and the areas under the plasma drug concentration-time curve from 0 to 0.5 h [AUC (0-0.5 h)], 0 to 1 h [AUC (0-1 h)], 0 to 2 h [AUC (02 h)], 0 to 10 h [AUC (0-10 h)], and from 0 to infinity (AUC). In addition, estimates of mean residence time (MRT) and terminal plasma half-life (tin) were obtained.
Glucose response Glucose response was characterized by determining the decremental areas under the plasma concentration-time curve from 0 to 0.5 h, 0 to 1 h, and from 0 to 2 h. In addition, the maximal decrease in concentration, together with the time to the maximal response, were determined.
Statistical methods Statistical analyses were made with the SYSTAT software package (SYSTAT Inc., Evanston, IL, USA). Glipizide concentration values were analysed by analysis of variance for repeated measurements. Student's t-test (two-tailed) for paired values was used to determine possible differences between the study phases. P < 0.05 was considered to be statistically significant. Results are expressed as means (SEM).
Resulls
Glipizide absorption S o d i u m b i c a r b o n a t e a c c e l e r a t e d glipizide a b s o r p t i o n , as r e f l e c t e d in s i g n i f i c a n t c h a n g e s in t i m e to p e a k , f r a c t i o n a l early A U C v a l u e s , lag t i m e a n d a b s o r p t i o n half-life (Fig. 1;
500-
700 600
E
@
400
'5_
500
*
-o
300
-
f3_
o~
200 •
o
200
o~
h'-
400-
0"~
500
100
13..
0
1 0 0v 0
0
1
2
3
4
5
7
10
Time ( h )
Fig.L Effect of sodium bicarbonate (3.0 g, ~---o) on the absorption of glipizide (5 mg) shown as plasma glipizide concentrations. Mean (SEM) of 6 subjects. *P < 0.05 compared to control (o--o)
0
t
I
I
I
I
I
I
1
2
3
4
5
7
10
Time (h)
Fig.2. Effect of aluminium hydroxide (1.0 g, H ) on the absorption of glipizide (5 rag) shown as plasma glipizide concentrations. Mean (SEM) of 7 subjects. (O---O) control
K. T. Kivist/3 and E J. Neuvonen: Absorption and effect of glipizide
385
Table 1. Effect of sodium bicarbonate 3.0 g and aluminium hydroxide 1.0 g on the pharmacokinetics of glipizide 5 mg. Mean (SEM) of 6 and 7 subjects, respectively Control NaHCO3 Control AI(OH)3 Peak time (h) 2.5 (0.22) 1.0 (0.21)" 2.3 (0.18) 2.4 (0.32) Absorption half-life (h) 1.2 (0.25) 0.27 (0.09)a 0.94 (0.18) 1.3 (0.28) Lag time (h) 0.28 (0.03) 0.22 (0.01)b 0.30 (0.03) 0.31 (0.06) Peak concentration (ng/ml) 497 (75.2) 613 (68.8) 508 (58.4) 451 (21.3) AUC ((~0.5) (ng-h-ml t) 12.2 (6.1) 78.5 (24.4)b 10.6 (5.4) 18.6 (8.9) AUC (0-1) (ng-h-ml
Eorop.a0Joorof 0a,
003169709100094I
@Springer-Verlag 1991
Differential effects of sodium bicarbonate and aluminium hydroxide on the absorption and activity of glipizide K. T. Kivistii and P. J. Neuvonen Department of Pharmacology,University of Turku, Turku, Finland Received: July 5, 1990/Accepted: October 4, 1990
Summary. The effects of sodium bicarbonate and aluminium hydroxide on the absorption and activity of glipizide have been studied in healthy volunteers in two randomized cross-over trials. After an overnight fast, 5 mg glipizide was given either with 150 ml water or with water containing 3.0 g sodium bicarbonate or 1.0 g aluminium hydroxide. Sodium bicarbonate significantly increased the A U C of plasma glipizide from 0 to 0.5 h, 0 to I h, and from 0 to 2 h (six-, four- and twofold, respectively). The time to peak concentration (tm~) fell from 2.5 h during the control phase to 1.0 h during the sodium bicarbonate phase. The absorption half-life (tma), lag time and mean residence time (MRT) were also significantly decreased. No significant change in peak plasma concentration (Cmax), total A U C or elimination half-life (tl/2) was noted. The decremental plasma glucose areas from 0 to i h and 0 to 2 h were significantly larger (80% and 50%, respectively) than during the control phase. The maximal decrease in glucose was 50% greater during the sodium bicarbonate phase, and the time to reach it was reduced by 35 rain. Aluminium hydroxide had no significant effects on the rate or extent of absorption of glipizide, and the glucose response also remained unaffected. It is concluded that the concomitant ingestion of sodium bicarbonate and glipizide may result in accelerated absorption of glipizide and an increased effect on glucose. A common dose of aluminium hydroxide did not appear to affect the absorption of glipizide. Key words: Glipizide, gastrointestinal absorption, sodium bicarbonate, aluminium hydroxide, glucose, drug interaction, healthy volunteers
Glipizide is absorbed completely and relatively rapidly, even though it is only sparingly soluble in the acidic gastric contents [1]. However, absorption of glipizide and other sulphonylure as may b e unusually slow in some healthy subjects, as well as in certain diabetic patients [2-4]. It is often recommended that sulphonylureas be taken 30 min before meals to ensure their rapid absorption [5]. For example,
food can delay the absorption of glipizide, and taking glipizide on an empty stomach has been shown to result in better disposition of glucose in diabetic patients [6]. Antacids affect the absorption of many drugs, and clinically important interactions have been described [7, 8]. The consequences of drug-antacid interactions are very dependent on the antacid used, but reduced absorption of the affected drug is most often encountered. Magnesium hydroxide and sodium bicarbonate may increase the rate of absorption of certain weakly acidic drugs, e.g. tolfenamic and mefenamic acids [9], and naproxen [10], respectively. On the other hand, aluminium hydroxide, alone or in combination with other antacids, typically reduces or delays drug absorption [10-12]. Recently, magnesium hydroxide was shown to accelerate the absorption and increase the glucose-lowering effect of glipizide (Kivist6 and Neuvonen, unpublished observations). There do not appear to be other published data about the possible effects of different antacids on the absorption of sulphonylureas. It was considered important to determine whether additional interactions could occur between these two widely used drug groups. In the present study, the effects of sodium bicarbonate and aluminium hydroxide on the gastrointestinal absorption and glucose response of glipizide have been studied in healthy volunteers.
Materials and methods
General design The present investigation comprised two separate studies. Six healthy volunteers participated in the first study and 7 in the second. All volunteers were considered healthy on the basis of medical history, physical examination, and routine laboratory tests (renal and hepatic function, fasting glucose, haemoglobin). The subjects were thoroughly informed, both verbally and in writing, and informed consent was obtained. The study protocol was accepted by the local Ethics Committee. A randomized cross-overdesign was employed, with two phases, at least one week apart. The test drugs were ingested after an over-
384
K. T. Kivist6 and E J. Neuvonen: Absorption and effect of glipizide
night fast together with 150 ml water or with 150 ml water containing the antacid studied. The subjects were kept supine, under direct medical supervision, for 2 h from the beginning of the study. No food was allowed during that time; breakfast was given after the 2 h blood sample, and then the subjects were allowed to move and eat as desired. Hypoglycaemic symptoms were monitored on the study days. Glucose both for oral and intravenous administration was available in case of severe hypoglycaemia. It was not needed. Timed venous blood samples from an indwelling catheter were collected in heparinized tubes 0,15,22, 30 and 45 min, and 1,1.5, 2, 3, 4, 5, 7 and 10 h after drug ingestion. The tubes were chilled on ice both before and after sample collection. Plasma was separated within 30 rain at + 4 °C, and the samples were stored at - 20 °C until analysed.
Effect of sodium bicarbonate on glipizide absorption One man and 5 women with a mean (SEM) age of 23 (0.8) y, and a mean body weight of 59 (2.8) kg, ingested 5 mg glipizide (Melizid, Medica, Finland) either with 150 ml water, or with 150 ml water containing 3.0 g sodium bicarbonate (NaHCO3; E.Merck, Darmstadt, West-Germany).
Effect of aluminium hydroxide on glipizide absorption Two men and 5 women with a mean (SEM) age of 23 (0.7) y, and a mean body weight of 61 (3.7) kg, ingested 5 mg glipizide (Melizid, Medica, Finland) either with 150 ml water, or with 150 ml water containing 1.0 g aluminium hydroxide (AI(OH)3; E. Merck, Darmstadt, West-Germany).
Analytical methods Plasma glipizide concentrations were determined by reversed phase HPLC, using a modified version of two previously published methods [13, 14]. To i ml plasma, 0.5 M HC1 0.2 ml and 400 ng tolbutamide, the internal standard, were added. The sample was then extracted with 5 ml of a 1 : 1 mixture of dichloromethane and hexane and shaken for 4 min. After centrifugation, the organic phase was evaporated to dryness under a stream of nitrogen at 40 °C. The residue was redissolved in 70 gl mobile phase, and a 20 ~tl aliquot was injected into the chromatograph. The mobile phase consisted of a mixture of methanol and 0.01 M phosphate buffer at pH 3.5 (55 : 45). The flow-rate was 1.2 ml. min- t. The UV detector was set at 229 nm, and the sensitivity was kept at 0.02 a. u. f. s. The inter-assay coefficient of variation was 4.4% (mean 218 ng-ml t, n = 8).
Plasma glucose concentrations up to the breakfast time (2 h) were determined by the glucose oxidase method (Reflotron, Boehringer Mannheim GmbH, West-Germany). The inter-assay coefficient of variation was 3.3% (mean 5.6 mmol. 1 1, n = 8).
Pharmacokinetic analysis The plasma concentration-time data for glipizide were fitted to an open one- or two-compartment model, whichever gave the better fit, by weighted least squares analysis, using the SIPHAR pharmacokinetic curve fitting programme (SIMED, Creteil, France). The absorption of glipizide was characterized by the peak time (tmax), halflife of absorption (tl/2a), lag time, peak plasma concentration ( C m a x ) , and the areas under the plasma drug concentration-time curve from 0 to 0.5 h [AUC (0-0.5 h)], 0 to 1 h [AUC (0-1 h)], 0 to 2 h [AUC (02 h)], 0 to 10 h [AUC (0-10 h)], and from 0 to infinity (AUC). In addition, estimates of mean residence time (MRT) and terminal plasma half-life (tin) were obtained.
Glucose response Glucose response was characterized by determining the decremental areas under the plasma concentration-time curve from 0 to 0.5 h, 0 to 1 h, and from 0 to 2 h. In addition, the maximal decrease in concentration, together with the time to the maximal response, were determined.
Statistical methods Statistical analyses were made with the SYSTAT software package (SYSTAT Inc., Evanston, IL, USA). Glipizide concentration values were analysed by analysis of variance for repeated measurements. Student's t-test (two-tailed) for paired values was used to determine possible differences between the study phases. P < 0.05 was considered to be statistically significant. Results are expressed as means (SEM).
Resulls
Glipizide absorption S o d i u m b i c a r b o n a t e a c c e l e r a t e d glipizide a b s o r p t i o n , as r e f l e c t e d in s i g n i f i c a n t c h a n g e s in t i m e to p e a k , f r a c t i o n a l early A U C v a l u e s , lag t i m e a n d a b s o r p t i o n half-life (Fig. 1;
500-
700 600
E
@
400
'5_
500
*
-o
300
-
f3_
o~
200 •
o
200
o~
h'-
400-
0"~
500
100
13..
0
1 0 0v 0
0
1
2
3
4
5
7
10
Time ( h )
Fig.L Effect of sodium bicarbonate (3.0 g, ~---o) on the absorption of glipizide (5 mg) shown as plasma glipizide concentrations. Mean (SEM) of 6 subjects. *P < 0.05 compared to control (o--o)
0
t
I
I
I
I
I
I
1
2
3
4
5
7
10
Time (h)
Fig.2. Effect of aluminium hydroxide (1.0 g, H ) on the absorption of glipizide (5 rag) shown as plasma glipizide concentrations. Mean (SEM) of 7 subjects. (O---O) control
K. T. Kivist/3 and E J. Neuvonen: Absorption and effect of glipizide
385
Table 1. Effect of sodium bicarbonate 3.0 g and aluminium hydroxide 1.0 g on the pharmacokinetics of glipizide 5 mg. Mean (SEM) of 6 and 7 subjects, respectively Control NaHCO3 Control AI(OH)3 Peak time (h) 2.5 (0.22) 1.0 (0.21)" 2.3 (0.18) 2.4 (0.32) Absorption half-life (h) 1.2 (0.25) 0.27 (0.09)a 0.94 (0.18) 1.3 (0.28) Lag time (h) 0.28 (0.03) 0.22 (0.01)b 0.30 (0.03) 0.31 (0.06) Peak concentration (ng/ml) 497 (75.2) 613 (68.8) 508 (58.4) 451 (21.3) AUC ((~0.5) (ng-h-ml t) 12.2 (6.1) 78.5 (24.4)b 10.6 (5.4) 18.6 (8.9) AUC (0-1) (ng-h-ml
