Bioavailability File: Glipizide Summary
Bioavailability File: Glipizide
Glipizide is a member of the second-generation sulfonylurea drugs used in the treatment of type 2 diabetes mellitus. It is completely absorbed from the gastrointestinal tract and metabolized into five different metabolites in the liver, and does not show the hypoglycemic activity by itself. It exhibits its hypoglycemic activity through pancreatic and extrapancreatic pathways.
Glipizide is 98% bound to plasma proteins and has a half-life between 2.5 and 4.7 hours. Cimetidine and ranitidine increase the plasma concentration of Glipizide approximately three times.
On the other hand, active charcoal may decrease the absorption of Glipizide. No effect of age or obesity exists on the absorption and bioavailability of Glipizide. In this paper, the physicochemical and pharmacological properties, determination methods and pharmacokinetics of Glipizide are reviewed.
Key Words: Glipizide, NIDDM, type II diabetes, pharmacokinetics, bioavailability.
Received : 09.01.2008 Revised : 13.02.2008 Accepted : 28.02.2008
INTRODUCTION
Non-insulin dependent diabetes mellitus (NIDDM) (type II diabetes) is a disorder characterized by an increase in hepatic glucose production and destruction of peripheral glucose intake1. The most common drugs prescribed for the stimulation of insulin release are the sulfonylureas2. Glipizide is a member of the second-generation sulfonylureas firstly synthesized in Italy in 19713. The hypoglycemic activity is nearly 100 times greater than of those belonging to the first generation of sulfonylureas. In 1984, with Glyburide, the manufacturers submitted this drug to the Food and Drug Administration (FDA) and it has been on
the market for more than 20 years4. It is well tolerated and no important side effect has been reported.
Physicochemical Properties
Glipizide was firstly synthesized in 1971 by Ambrogi et al.5-7, and belongs to the second-generation sulfo- nylurea drugs8,9. It was derivatized by the addition of a cyclohexyl group to the main structure of sulfo- nylurea and substitution of a non-polar group to the phenyl circle3. The chemical structure is 1- cyclohexyl- 3- [[p- [2- (5- methylpyrazinecarboxamido) ethyl]
*°
phenyl] sulfonyl] urea7,10. The molecular formula of Glipizide is C21H27N5O4S (Fig. 1) with the molecular weight 445.54 g/mol11-13.
Glipizide is a white odorless crystalline powder with a melting point at 208°-209°C13-16. It is insoluble in water and alcohol12,14-16, and slightly soluble in acetone14-16. On the other hand, it is soluble in meth- ylene chloride12, chloroform14-16, freely soluble in dilute alkali hydroxides15,16 and dimethyl formamide16. It is 98% bound to plasma proteins16
and has a pKa=5.9, making it a weak acidic drug17. Identification and Quantification Methods
Since Glipizide is used at very low doses, highly sensitive methods for the determination of Glipizide have been investigated in the literature18. For the determination of Glipizide from plasma and pharma- ceutical dosage forms, high pressure liquid chroma- tography (HPLC)19-24, thin layer chromatography (TLC)25, liquid chromatography (LC)26-28, capillary electrophoresis29, radioimmunoassay30,31, and UV spectrophotometry11,32-35 have been previously eval- uated. The sensitivity of HPLC was 5 ng/ml36 and Lin et al.27 developed a liquid chromatography-mass spectrometric (LC-MS)/MS method with a lower limit of quantification (LLOQ) of 1 ng/ml.
Glipizide has the maximum absorbancy at λ=276 nm (aqueous acid A11=231a11,16. The effects of pH and surfactants on the dissolution properties of Glipizide wer e investigated by Jamzad et al.32 by using UV spectrophotometry λ=276nm. The same determination method was also used for the investigation of release characteristics of Glipizide from pellet formulations33, matrix tablets37,38, osmotic tablets with cyclodextrins39,
and mucoadhesive microspheres34. On the other hand, the release of Glipizide from lipospheres has been characterized by UV spectrophotometer at λ=223 nm by Shivakumar et al.35.
Becker et al.20 used HPLC method equipped with a fluorometric detector for the quantification of Glipiz- ide. Feely et al.21 used the same method for the determination of Glipizide from plasma with tolbuta- mide as the internal standard. For the determination of Glipizide from breast milk, Feig et al.40 evaluated an HPLC method with fluorometric detection (exci- tation=470 nm, emission=530 nm) with limit of detec- tion (LOD) 0.005 µg/ml.
The determination of Glipizide from plasma has been evaluated by using a HPLC method by Wahlin-Boll et al.19, and many researchers have used the same method with some slight modifications17,36,41-48. The determination of Glipizide from plasma after admin- istration of its combined dosage forms with metformin has been done again by using HPLC-UV method (λ=225 nm) following a solid phase extraction tech- nique. The LOD and LOQ of this method were 4.5 ng/ml and 7.5 ng/ml, respectively22 . The determina- tion of Glipizide with six other anti-diabetic drugs from pharmaceutical dosage forms and plasma has been investigated with suitable gradient systems with the same HPLC-UV method (λ=260 nm). No extraction method has been used for the pharmaceutical dosage forms, but on the other hand, a simple extraction with acetonitrile has been employed for the plasma samples49.
Maggi et al.30 used the radioimmunoassay method for the determination of Glipizide from plasma. This method was also used in another study by Huup- ponen et al.31 in which they have investigated the effect of guar gum on the bioavailability of Glipizide in humans.
For the determination of unbound Glipizide in plasma, a LC-tandem mass spectrometry (LC-MS-MS) method was investigated. Samples of 0.2 ml were extracted and analyzed with high pressure liquid chromatog- raphy-tandem mass spectrometry (m/z 446/321) with
Figure 1. The structural formula of Glipizide12.
an LOD of 1 ng/ml27. Ho et al.26 investigated another LC-MS (m/z 321) method for the determination of Glipizide in plasma and urine samples in horses and the LOD of this method was found as 1 ng/ml. These two methods involve extraction procedures. Because of the long retention time (20 min) of Glipizide, Ding et al.28 developed a new LC-MS/MS analysis method.
In this method, organic solvent was added to plasma samples in order to precipitate the proteins and the retention time was 2 min for Glipizide. The LLOQ of this new method was found as 0.004 µg/ml.
Pharmacology Mechanism of Action
The major pharmacological effects of the drug sub- stances belonging to the class of sulfonylureas may be classified as extra pancreatic and pancreatic activ- ities and the modification of the other systems3. The mechanism of action of Glipizide is given in Table 150.
Pancreatic activity
Many studies revel that drugs belonging to the class of sulfonylureas stimulate the secretion of insulin
from the pancreatic beta cells existing in the liver7,51- 53. The intrinsic insulin release capacity of Glipizide is 100 times more than that of the first generation sulfonylureas54-57. In the rat pancreas perfusion study by Artini et al.56, the tissues were separately perfused with Glipizide and Glyburide for 15 min. Insulin release was immediately achieved with Glipizide and reached a maximum level in 5 min (Fig. 2). Twenty minutes after the end of perfusion with Glipizide, the level of insulin returned to its basal level. In another study, by Barr et al.58, dogs were randomly allocated into three groups as follows: Group 1: 80% proximal pancreatectomy; Group 2: Proximal pancreatectomy plus splenocaval diversion; Group 3: Control. After administration of Glipizide (5 mg, oral, twice daily), no effects on insulin secretion after the loss of beta cell amount and glucose handling were found. Al- though Glipizide’s exact mechanism of action in affecting the release of insulin from beta cells is un- known, it is a common thought that due to the changes in the cellular flux of sodium and calcium ions, specific binding to the cellular membrane is responsible59,60. Glipizide shows its effect by increasing the sensitivity of beta cells in the liver to glucose. Hence, insulin release but not insulin synthesis is increased in all glucose levels61. Marco et al.62 found no difference in glucagon secretion after a seven-day administration of Glipizide to healthy volunteers.
Extrapancreatic activity
The extrapancreatic activity of the sulfonylurea drugs has been investigated by many researchers63-65. In healthy animals and diabetic patients, the extrapan- Table 1. The hypoglycemic activity mechanisms
of Glipizide50
Site of action Mechanism of action Pancreatic activity Regulation of insulin release
Decrease glucagon secretion Extrapancreatic activity Regulation of the sensitivity
of the tissue to insulin Direct
Increase receptor binding Regulation of activity following binding Indirect
Regulation of hyperglycemia Decrease the concentration of the plasma free fatty acids Decrease the hepatic insulin secretion
Figure 2. Effect of equal molar concentrations of Glipizide and Glyburide (Glibenclamide) on the release of insulin from isolated rat pancreas56.
creatic as well as pancreatic activity of Glipizide has been evaluated. These effects increase the peripheral and hepatic activity of endogenous and exogenous insulin. A statistical difference in hypoglycemia was investigated between two groups of animals, with the first group receiving low-dose Glipizide and the second receiving low-dose insulin as the control group. In addition, insulin receptors in the hepatic plasma membrane increased 2.5 times more with respect to the control group65. NIDDM patients treated with Glipizide showed increased responses to insulin, increased peripheral glucose uptake and suppression of hepatic glucose production66,67.
Uses and Administration
Most of the patients with NIDDM are treated with 5- 20 mg/day Glipizide administration3,8,68,69. It is recommended for 15 mg/day patients to take the drug 30 min before breakfast and for >15 mg/day patients to take the first portion as half of the total dose 30 min before breakfast and second portion 30 min before dinner. The blood glucose level must be monitored carefully in patients crossing over the insulin therapy to the Glipizide therapy. Low-dose of insulin (<20 U/d) may be exchanged with 5 to 10 mg/day Glipizide. If there is a problem with insulin treatment or if patients with NIDDM can be well controlled with Glipizide, insulin treatment should be replaced by Glipizide treatment3.
Side Effects
Although many studies indicate that Glipizide is side- effect free70-72, some researchers have reported certain side effects, including some gastrointestinal side effects such as diarrhea, vomiting, nausea and abdom- inal pain73-75, some skin reaction characterized by rashes75 and alcohol-induced flushing76 and hypoglycemia10,77.
Pharmacokinetics and Bioavailability Absorption
Glipizide is completely and rapidly absorbed from
the gastrointestinal channel47,78,79. The maximum plasma concentration is reached after 1.2-3.5 hours following oral administration80-85. In the patients with NIDDM, the plasma concentration was found in a range of 540-1644 nmol/L and the mean plasma concentration was calculated as 1020 and 1093 nmol/L80,85. After high doses, such as 0.1 mg/kg and 10 mg, the mean plasma level was found as 2050 and 2259 nmol/L80,81. The absorption of Glipizide is delayed if it is taken together with food (Fig. 3)50,78. According to this result, Glipizide must be taken 30 min before meals.
Glipizide is adsorbed by active charcoal and this significantly prevents its gastrointestinal absorption86. In a crossover study, 6 male volunteers (age: 28±4 years and weight: 76±4 kg) received 5 mg Glipizide (Control), 5 mg Glipizide + 8 g cholestyramine (Group 1) and 10 mg Glipizide + 8 g activated charcoal (Group 2). The Cmax and AUC(0-10) values of the experimen- tal groups decreased, but on the other hand, no sig- nificant change in the tmax was observed (Table 2)44.
Figure 3. Effect of food on the plasma concentration of Glipizide (n=14 NIDDM patients)50.
Table 2. The effect of active charcoal and cholestyramine on the absorption of Glipizide44
Control Cholestyramine Charcoal
Cmax
(ng/ml)
425±36 285±31a
89±31a
tmax
(h)
1.3±0.33 1.9±0.41 1.0±0.22
AUC(0-10h)
(ng.h/ml)
1830±267 1260±145a 352±128a
Relative Bioavailability
(% of control) 100 71 (59-83)
19 (8-37)
aSignificantly different (p<0.01) from control group (Student’s paired t-test, two-tailed)
n=6 mean±s.e.
Kivistö et al.17,45 investigated the possible effects of antacid drugs (NaHCO3, Al(OH)3, Mg(OH)2) on the absorption and other pharmacokinetic parameters of Glipizide (Fig. 4) (Table 3). No effect of aluminum hydroxide on the absorption of Glipizide was found, whereas sodium bicarbonate and magnesium hydrox- ide accelerated the absorption of Glipizide as well as the effect of Glipizide on glucose level.
The plasma concentration of Glipizide is increased when it is used in combination with H2 receptor antagonists such as ranitidine and cimetidine. Cime- tidine and ranitidine increased AUC values of Glip- izide from 2267±387 ng.h/ml to 2792±704 ng.h/ml and from 2947±508 ng.h/ml to 3953±601 ng.h/ml, respectively (P<0.05). No differences in the elimination half- life and protein binding were observed21. The a b s o r p t i o n o f G l i p i z i d e w a s d e l a y e d (AUC=5251±1383nmol.h/L to 6547±980nmol.h/L, P<0.05) and elimination half-life of Glipizide insignif- icantly prolonged (t1/2=2.8±0.5h to 3.3±0.5h, NS) when combined with indobufen, a nonsteroidal anti- inflammatory drug87.
In another study investigating the effect of age, dia- betes, and multiple dosing regimens on Glipizide pharmacokinetics, no changes in tmax, Cmax, AUC, Cl, Vss, Varea, and t1/2 values were found. On the other hand, in all groups, a statistically significant difference was observed in fp(free fraction of drug)43.
Similar to this result, no effect of obesity was reported by Jaber et al.46. Additionally, guar gum had no harmful effect on the absorption of Glipizide when given either with the drug or half an hour later with breakfast31.
The oral bioavailability of Glipizide increases when the extended release dosage forms are compared with the conventional tablet forms. Elementary osmotic pump (EOP) tablets and bilayered matrix tablets prepared with hydroxypropylmethylcellulose (HP- MC) were compared with conventional Glipizide tablets through AUC values obtained from profiles of time versus plasma concentrations of Beagle dogs (Fig. 5). The bioavailability of the EOP tablets were recorded as 102.8% when compared with conventional tablet dosage forms88.
The Cmax and AUC values of Glipizide are three times more than those of glibenclamide, which is also another member of the sulfonylurea drugs (Table 4, Fig. 6)41.
Distribution
The volume of distribution of Glipizide was calculated by the administration of both radiolabelled and un- labelled Glipizide in humans. Three healthy volunteers received oral 5 mg C14-Glipizide and volume of dis- tribution was calculated as 20.4 L82. In two different Table 3. Effect of sodium bicarbonate (3.0 g)45 , aluminium hydroxide (1.0 g)45 and magnesium hydroxide
(0.85 g)17 on the pharmacokinetics of Glipizide (5 mg)
tmax (h) t1/2abs (h) Lag time (h) Cmax (ng/ml) AUC0-1/2 (ng.h/ml) AUC0-1 (ng.h/ml) AUC0-2 (ng.h/ml) AUC0-10 (ng.h/ml) AUC (ng.h/ml) MRT (h) t1/2 (h)
a P<0.01 b P<0.05 compared to control.
Control 2.5±0.22 1.2±0.25 0.28±0.03 497±75.2 12.2±6.1 73.1±20.7
346±111 2330±393 3540±922 8.3±2.0 4.8±1.4
NaHCO3
1.0±0.21a
0.27±0.09a 0.22±0.01b
613±24.4b
78.5±24.4b 316±42.7a
837±87.5a
2490±443 3240±841 6.1±1.7a
4.2±1.6
Control 2.3±0.18 0.94±0.18 0.30±0.03 508±58.4 10.6±5.4 69.6±17.6
387±82.9 2230±347 3250±832 7.3±1.8 4.2±1.3
Al(OH)3
2.4±0.32 1.3±0.28 0.31±0.06
451±21.3 18.6±8.9 88.5±32.9
341±81.7 2041±268 2730±629 6.4±1.1 3.2±0.66
Control 1.6±0.32 0.32±0.06
- 416±26.7 27.0±10.5 155±40.4
- 1665±198 2048±383 5.6±0.85
3.4±0.7
Mg(OH)2
1.2±0.29 0.15±0.02b
- 445±32.0 75.2±19.4b
262±36.9b
- 1718±167 2025±300 4.9±0.57 3.1±0.35
Figure 4. Effect of sodium bicarbonate (A- 1.0 g solid circles n=6)45, aluminium hydroxide (B- 3.0 g solid circles n=7)45 and magnesium hydroxide (C- 0.85 g solid circles n=8)17 on absorption of Glipizide (5 mg), shown as plasma Glipizide concentrations (mean±SE), compared with the control group (open circles). *P<0.05
Figure 5. Plasma Glipizide concentration in beagle dogs (n=6) (◆ conventional tablets, ▲ EOP, ■ matrix tablet) 88.
Table 4. Pharmacokinetic parameters of
Glibenclamide and Glipizide in 14 type 2 diabetic patients after intake of 10 mg each drug in the morning41
* P<0.001
Glibenclamide Glipizide
Cmax (After 2h) nmol/L
615±66 1865±214*
AUC 1099±327 2820±708*
Figure 6. Serum concentration profiles (mean±SD) of Glibenclamide and Glipizide in 15 type 2 diabetic patients after intake of 10 mg each drug in the morning (Solid line=Glipizide, dotted line=Glibenclamide)41.
studies, the volume of distribution was found as 5.0 L89 and 6.7 L90 for Glipizide. Schmidt et al.83 found volume of distribution as 11.1 L, corresponding to 15% of the total body weight. In rats receiving C14–- labeled Glipizide, the total radioactivity was deter- mined in blood and highly perfused organs91.
Pentikainen et al.84 calculated the volume of distribu- tion as 12 L and the red blood cellular uptake of
Glipizide as very low levels. For the use of Glipizide in breastfeeding mothers, conventional tablet dosage forms were administered and no drug was determined in the milk, so it was concluded that mothers may safely use Glipizide during this period40.
Metabolism and Elimination
The half-life of Glipizide is very short (2.5-4.7 hours)
when compared with the other drugs in the sulfony- lurea group79-85,90. Although not in all of the studies, the calculations were investigated according to the two compartmental models. Glipizide is mainly me- tabolized in the liver82-85. Five percent of the total dose is introduced to the first pass metabolism effect82- 84. Seventy-two to 85% of the total drug is excreted as unchanged and the rest is metabolized to its five inactive metabolites in the liver82,83 . These metabolites are 4-trans-hydroxy-cyclohexyl form, 3-cis-hydroxy- cyclohexyl form, N-(2-acetylamino-ethyl-phenyl- sulphonyl)N’-cyclohexyl urea (DCDA) form and two unidentified metabolites76,82,83,91. Sixty-five to 68%
of the total amount of Glipizide (5% unchanged) is excreted in the urine in 24 h. Fifteen percent of the total dose is excreted in the feces80-82. As a result, Glipizide is either hydroxylated or transformed into its conjugated forms in the liver and rapidly excreted by the kidneys3.
Formulation Types
The conventional tablet dosage forms and osmotic tablets of Glipizide exist as commercially available forms. The release of Glipizide from osmotic tablets92, cyclodextrin complex osmotic tablets39 and controlled release tablets prepared with HPMC38 fits zero order kinetics. In addition, bilayered tablets prepared with HPMC, elementary osmotic tablets88, lipospheres35
and mucoadhesive tablets34 are among other available dosage forms.
Conclusion
Glipizide is still the most common drug used in the treatment of NIDDM. Rapid absorption from the gastrointestinal channel, high antidiabetic potential, and variability in the antidiabetic mechanisms make Glipizide a favorite drug from the treatment perspec- tive. The most important property of Glipizide is the decrease in absorption when it is taken with food.
Furthermore, it does not exist in the breast milk and no serious side effect has been reported to date. As a result of this review, it can be concluded that with elevation in the duration time of Glipizide in the blood circulation, it will become a more forthcoming
drug in the sulfonylurea class of drugs.
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