151

FABAD J. Pharm. Sci., 31, 151-161, 2006

SCIENTIFIC REVIEW

Bioavailability File: GlipizideSummary

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 : 09.01.2008Revised : 13.02.2008Accepted : 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]

*°

152

Kaynak, Öner

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.

153

FABAD J. Pharm. Sci., 31, 151-161, 2006

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 mechanismsof 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.

154

Kaynak, Öner

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 andcholestyramine on the absorption ofGlipizide44

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.

155

FABAD J. Pharm. Sci., 31, 151-161, 2006

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

156

Kaynak, Öner

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 ofGlibenclamide and Glipizide in 14 type 2diabetic patients after intake of 10 mg eachdrug 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)

157

FABAD J. Pharm. Sci., 31, 151-161, 2006

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.

REFERENCES

1. Allen BT, Feinglos MN, Lebovitz HE. Treatment

of poorly regulated non-insulin-dependent dia-

betes mellitus with combination insulin-

sulfonylurea, Arch Intern Med, 145, 1900-1903,

1985.

2. Hsieh SH, Lin JD, Cheng HY, Ho C, Liou MJ.

Sustained-release versus immediate-release glip-

izide for treatment of type 2 diabetes mellitus in

Chinese patients: a randomized, double-blind,

double-dummy, parallel-group, 12-week clinical

study, Clin Ther. , 28, 1318-1326, 2006.

3. Lebovitz HE. Glipizide: a second-generation sul-

fonylurea hypoglycemic agent, Pharmacotherapy,

5, 63-77, 1985.

4. Kennedy DL, Piper JM, Baum C. Trends in use of

oral hypoglycemic agents 1964-1986, Diabetes

Care,11, 558-562, 1988.

5. Ambrogi V, Bloch K, Daturi S, Griggi P, Logemann

W, Parenti MA, Rabini T, Tommasini R. New oral

antidiabetic drugs part I, Arzneim Forsch, 21, 200-

204, 1971.

6. Ambrogi V, Bloch K, Cozzi P, Daturi S, Logemann

W, Parenti MA, Tommasini R. New oral antidia-

betic drugs part II, Arzneim Forsch, 21, 204-208,

1971.

7. Ambrogi V, Bloch K, Daturi S, Griggi P, Logemann

W, Mandelli V, Parenti MA, Rabini T, Usardi MM,

Tommasini R. Pharmacological study on a new

oral antidiabetic: N-(4-(_-(5-methyl-pyrazine-2-

carboxamido)-ethyl)-benzene-sulphonyl)-N’-

cyclohexyl-urea or K4024, Arzneim Forsch, 21, 208-

215, 1971.

8. Leeuw DI, Baere HD, Decraene P, Lemmens P,

Verhaegen H. An open comparative study of the

efficacy and tolerance of a new antidiabetic agent

glipizide, Diabetologia, (Suppl) 9, 364-366, 1973.

9. Teagarden JR. Glyburide and glipizide: clinical

profile of two new oral hypoglycemic agents,

Hosp Formul., 21, 313-331, 1986.

10. Masbernard A, Guidicelli C, Massey J. Clinical

experience with glipizide in the treatment of most-

ly complicated diabetes, Diabetologia, (Suppl) 9,

356-363, 1973.

158

Kaynak, Öner

11. The United States Pharmacopeia 29, USA: Twin-

brook Parkway, Rockville MD 20852, 1002-1004,

2006.

12. European Pharmacopoeia 5th ed. Council of Eu-

rope, France: 67075 Strasbourg Cedex, 1662-1663,

2004.

13. The Merch Index, 13th ed. Emeritus S (ed), Merck

Co Inc., USA, 790, 2001.

14. British Pharmacopoeia. HMSO, United Kingdom,

306-307, 1993.

15. Martindale The Extra Pharmacopoiea, 29th ed.

Reynolds JEF (ed), The Pharmaceutical Press, En-

gland, 390, 1989.

16. Clarke’s Isolation and Identification of Drugs, 2nd

ed. Moffat AC (ed), The Pharmaceutical Press, Great

Britain, 640-641, 1986.

17. Kivistö KT, Neuvobeb PJ. Enhancement of absorp-

tion and effect of glipizide by magnesium hydrox-

ide, Clin Pharmacol Ther, 49, 39-43, 1991.

18. Ghoneim EM, El-Attar MA, Hamam E, Khashaba

PY. Stripping voltammetric quantification of the

anti-diabetic drug glipizide in bulk form and

pharmaceutical formulations, J Pharmaceut Biomed,

43, 1465-1469, 2007.

19. Wahlin-Boll E, Melander A. HPLC determination

of glipizide and some other sulfonylurea drugs

in serum, J Cromatogr, 164, 541-546, 1979.

20. Becker R. Fluorometric determination of glibornu-

ride in plasma and serum using 7-chloro-4-

nitrobenzo-2-oxa-1,3-diazole, Arzneim Forsch, 27,

102-105, 1977.

21. Feely J, Collins WC, Cullen M, El-Debani AH,

Macwalter RS, Peden NR, Stevenson IH. Potenti-

ation of the hypoglycaemic response to glipizide

in diabetic patients by histamine H2-receptor

antagonists, Br J Clin Pharmacol, 35, 321-323, 1993.

22. AbuRuz S, Millership J, McElnay J. The develop-

ment and validation of liquid chromatography

method for the simultaneous determination of

metformin and glipizide, gliclazide, glibenclamide

or glimperide in plasma, J Chromatogr B Analyt

Technol Biomed Life Sci, 817, 277-286, 2005.

23. Emilsson H. HPLC determination of glipizide in

human plasma or urine, J Chromatogr, 421, 319-

326, 1987.

24. Yao J, Shi YQ, Li ZR, Jin SH. Development of a

RP-HPLC method for screening potentially coun-

terfeit anti-diabetic drugs, J Chromatogr B Analyt

Technol Biomed Life Sci, 853, 254-259, 2007.

25. El-Kousy NM. Stability-indicating densitometric

determination of some antidiabetic drugs in dos-

age forms, using TLC, Mikrochim Acta, 128, 65-68,

1998.

26. Ho EMN, Yiu KCH, Wan TSM, Steward BD, Wat-

kins KL. Detection of anti-diabetics in equine

plasma and urine by liquid chromatography-

tandem mass spectrometry, J Chromatogr B Analyt

Technol Biomed Life Sci, 811, 65-73, 2004.

27. Lin ZJ, Desai-Krieger D, Shum L. Simultaneous

determination of glipizide and rosiglitazone un-

bound drug concentration in plasma by equilib-

rium dialysis and liquid chromatography-tandem

mass spectrometry, J Chromatogr B Analyt Technol

Biomed Life Sci, 801, 265-271, 2004.

28. Ding CG, Zhou Z, Ge QH, Zhi XJ, Ma LL. Simul-

taneous determination of metformin and glipizide

in human plasma by liquid chromatography-

tandem mass spectrometry, Biomed Chromatogr,

21, 132-138, 2007.

29. Strausbauch MA, Xu SZ, Ferguson JE, Nunez M,

Machacek D, Lawson GM, Wettsein PJ, Landers

JP. Concentration and analysis of hypoglycemic

drugs using solid phase extraction-capillary elec-

trophoresis, J Chromatogr A, 717, 279-291, 1995.

30. Maggi E, Pianezzola E, Valzelli G. Radioimmu-

noassay of glipizide in human plasma, Eur J Clin

Pharmacol, 21, 251-255, 1981.

31. Huupponen R, Karhuvaara S, Seppala P. Effect of

guar gum on glipizide absorption in man, Eur J

Clin Pharmacol, 28, 717-719, 1985.

32. Jamzad S, Fassihi R. Role of surfactant and pH on

dissolution properties of fenofibrate and glipizide-

a technical note, AAPS PharmSciTech, 7, E1-E6,

2006.

33. Kaynak MS, Kafl HS, Öner L. Formulation of

controlled release glipizide pellets using pan

coating method. Proceed 10th Inter Pharm Technol

Symo (IPTS-2000), Sept. 11-13; 104-105, 2000.

34. Patel JK, Patel RP, Amin AF, Patel MM. Formulation

and evaluation of mucoadhesive glipizide micro-

spheres, AAPS PharmSciTech, 6, E49-E55, 2005.

35. Shivakumar HN, Patel PB, Desai BG, Ashok P,

159

FABAD J. Pharm. Sci., 31, 151-161, 2006

Arulmozhi S. Design and statistical optimization

of glipizide loaded lipospheres using response

surface methodology, Acta Pharm, 57, 269-285,

2007.

36. Bitzén PO, Melander A, Scherstén B, Svensson M,

Wahlin-Boll E. Long-term effects of glipizide on

insulin secretion and blood glucose control in

patients with non-insulin-dependent diabetes

mellitus, Eur J Clin Pharmacol, 42, 77-83, 1992.

37. Kaynak MS, Kafl HS, Öner L. A comparative study

on controlled release hydrophilic matrix tablets

containing glipizide. Proceed 11th Inter Pharm

Technol Symo (IPTS-2002), Sept. 9-11; 211-212, 2002.

38. Jamzad S, Fassihi R. Development of a controlled

release low dose class II drug-glipizide, Int J Pharm,

312, 24-32, 2006.

39. Gan Y, Pan W, Wei M, Zhang R. Cyclodextrin

complex osmotic tablet for glipizide delivery, Drug

Dev Ind Pharm, 28, 1015-1021, 2002.

40. Feig DS, Briggs GG, Kraemer JM, Ambrose PJ,

Moskovitz DN, Nageotte MN, Donat DJ, Padilla

G, Wan S, Klein J, Koren G. Transfer of glyburide

and glipizide into breast milk, Diabetes Care, 28,

1851-1855, 2005.

41. Groop l, Wahlin-Boll E, Groop PH, Tötterman KJ,

Melander A, Tolppanen EM, Fyhrqvist F. Pharma-

cokinetics and metabolic effect of glibenclamide

and glipizide in type 2 diabetics, Eur J Clin Phar-

macol, 28, 697-704, 1985.

42. Wahlin-Boll E, Groop L, Karhumaa S, Groop PH,

Tötterman KJ, Melander A. Therapeutic equiva-

lence of once- and thrice-daily glipizide, Eur J Clin

Pharmacol, 31, 95-99, 1986.

43. Kradjan WA, Kobayashi KA, Bauer LA, Horn JR,

Opheim KE, Wood FJ. Glipizide pharmacokinetics:

effect of age, diabetes and multiple dosing, J Clin

Pharmacol, 29, 1121-1127, 1989.

44. Kivistö KT, Neuvonen PJ. The effect of

cholestyramine and activated charcoal on glipizide

absorption, Br J Clin Pharmacol, 30, 733-736, 1990.

45. Kivistö KT, Neuvonen PJ. Differential effects of

sodium bicarbonate and aluminium hydroxide

on the absorption and activity of glipizide, Eur J

Clin Pharmacol, 40, 383-386, 1991.

46. Jaber LA, Ducharme MP, Halapy H. The effect of

obesity on the pharmacokinetics and pharmaco-

dynamics of glipizide in patients with non-insulin-

dependent diabetes mellitus, Ther Drug Monit, 18,

6-13, 1996.

47. Balant L. Clinical pharmacokinetics of sulphony-

lurea hypoglycaemic drugs, Clin Pharmacokinet,

6, 215-241, 1981.

48. Shenfield GM, Boutagy JS, Webb C. A screening

test for detecting sulphonylureas in plasma, Ther

Drug Monit, 12, 393-397, 1990.

49. Venkatesh P, Harisudhan T, Choudhury H, Mul-

langi R, Srinivas NR. Simultaneous estimation of

six anti-diabetic drugs-glibenclamide, gliclazide,

glipizide, pioglitazone, repaglinide and rosiglita-

zone: development of a novel HPLC method for

use in the analysis of pharmaceutical formulations

and its application to human plasma assay, Biomed

Chromatogr, 20, 1043-1048, 2006.

50. Wahlin-Boll E, Melander A, Sartor G, Schersten

B. Influence of food intake on the absorption and

effect of glipizide in diabetics and in healthy

subjects, Eur J Clin Pharmacol, 18, 279-283, 1980.

51. Marchetti P, Navalesi R. Pharmacokinetic-

pharmacodynamic relationships of oral hypogly-

caemic agents. An update, Clin Pharmacokinet, 16,

100-128, 1989.

52. Shunam CR. Glipizide: an overview, Am J Med,

30, 55-59, 1983.

53. Gaines KL, Hamilton S, Boyd AE. Characterization

of the sulfonylurea receptor on beta cell mem-

branes, J Biol Chem, 263, 2589-2592, 1988.

54. Brogden RN, Heel RC, Pakes GE, Speight TM,

Avery GS. Glipizide: a review of its pharmacolog-

ical properties and therapeutic use, Drugs, 18, 329-

353, 1973.

55. Herchuelz A, Malaisse WJ. Insulinotropic potency

of glipizide in vitro, Diabetologia, (Suppl) 9, 309-

310, 1979.

56. Artini D, Abbiati R, Orsini G, Parenti MA, Bloch

K, Daturi S, Mandelli W. Pharmacodynamic as-

pects of two sulfonylurea derivatives, glipizide

and glibenclamide, Diabetologia, (Suppl) 9, 311-

316, 1973.

57. Loubatieres-Mariani MM. Glipizide: experimental

study and comparison with other sulfonylureas,

Acta Endocrinol, (Suppl) 239, 26-32, 1980.

58. Barr JD, Parish ES, Krusch DA, Farris AH,

160

Kaynak, Öner

Freedlender AH, Kaiser DL, Hanks JB. Effect of

glipizide on the surgically altered pancreas, Am

J Surg, 157, 103-108, 1989.

59. Kaubisch N, Hammer R, Wollheim C, Renold AE,

Offord RE. Specific receptors for sulfonylureas in

brain and _ cell tumor of the rat, Biochem Pharmacol,

31, 1171-1174, 1982.

60. Lebovitz HE. Cellular loci of sulfonylurea actions,

Diabetes Care, (Suppl) 7, 67-71, 1984.

61. Grodsky GM, Epstein GH, Fanska R, Karam JH.

Pancreatic action of sulfonylureas, Fed Proc, 36,

2714-2719, 1977.

62. Marco J, Valverde I. Unaltered glucagon secretion

after seven days of sulfonylurea administration

in normal subjects, Diabetologia, (Suppl) 9, 317-

319, 1973.

63. Joost HG. Extrapancreatic effects of hypoglycemic

sulfonylureas: still a controversial issue, Tips June,

239-241, 1985.

64. Beck-Nielsen H, Hotler-Nielsen O, Pedrson O.

Mechanism of action of sulfonylureas with special

reference to the extrapancreatic effect on overview,

Diabetic Med, 5, 613-620, 1988.

65. Feinglos MN, Lebovitz HE. Sulphonylureas in-

crease the number of insulin receptors, Nature,

276, 184-185, 1978.

66. Lebovitz HE, Feinglos MN, Bucholtz HK, Lebovitz

FL. Potentiation of insulin action: a probable

mechanism for the anti-diabetic action of sulfony-

lurea drugs, J Clin Endocrinol Metab, 45, 601-601,

1977.

67. Greenfield MS, Doberne L, Rosenthal M, Schulz

B, Widstorm A, Reaven GM. Effect of sulfonylurea

treatment on in vivo insulin secretion and action

in patients with non-insulin-dependent diabetes

mellitus, Diabetes, 31, 307-312, 1982.

68. Peden N, Newton RW, Feely J. Oral hypoglycaemic

agents, Br Med J (Clin Res Ed), 286, 1564-1567, 1983.

69. Marigo S, Nevo GD, Bini PP, Sacchetti G. Pharma-

cological methods for evaluating a new hypogly-

caemic agent in humans: a multistep design, Arz-

neim Forsch, 21, 215-220, 1971.

70. Persson G. Clinical study with glipizide, a new

oral antidiabetic drug, Diabetologia, (Suppl) 9, 348-

350, 1973.

71. Johannessen A, Fagerberg SE. Glipizide, a new

oral antidiabetic agent, Diabetologia, (Suppl) 9,

339-347, 1973.

72. Pedrazzi F, Ceretti AP, Losi S, Bommartini F, Artini

D, Emanueli A. Evaluation in hospitalized subjects

of new hypoglycaemic sulfonylur ea, glydiazina-

mide, Arzneim Forsch, 21, 220-225, 1971.

73. Lahon HJF, Mann RD. Glipizide. Results of a

multicentre clinical trial, J Int Med Res, 1, 608-615,

1973.

74. Fowler LK. Glipizide in the treatment of maturity

onset diabetes: a multicentre out patient study,

Curr Med Res Opin, 5, 418-423, 1978.

75. Emanueli A, Molari E, Colombo PL, Caputo G.

Glipizide-a new sulfonylurea in the treatment of

diabetes mellitus, Arzneim Forsch, 22, 1881-1885,

1972.

76. Frederiksen PK, Mogensen EF. A clinical compar-

ison between glipizide (glibenase) and glibencla-

mide (daonil) in the treatment of maturity-onset

diabetes: a controlled double-blind crossover

study, Curr Ther Res, 32, 1-6, 1982.

77. Blohme G, Branegard B, Fahlen M, Marin P. Glip-

izide induced severe hypoglycemia, Acta Endocri-

naol, (Suppl 245) 9B, 13, 1981.

78. Sartor G, Schersten B, Melander A. Effects of

glipizide and food intake on the blood levels of

glucose and insulin in diabetic patients, Aca Med

Scand, 203, 211-214, 1978.

79. Melander A, Wahlin-Boll E. Clinical pharmacology

of glipizide, Am J Med, 30, 41-45, 1983.

80. Ostman J, Christenson I, Jansson B, Weiner L. The

anti-diabetic effect and pharmacokinetic properties

of glipizide, Acta Med Scand, 210, 173-180, 1981.

81. Peterson CM, Sims RV, Jones RL, Rieders F. Bio-

availability of glipizide and its effect on blood

glucose and insulin levels in patients with non-

insulin-dependent diabetes, Diabetes Care, 5, 497-

500, 1982.

82. Balant L, Zahnd G, Gorgia A, Schwardz R, Fabre

J. Pharmacokinetics of glipizide in man: influence

of renal insufficiency, Diabetologia, (Suppl) 9, 331-

338, 1973.

83. Schimidt HAE, Schoog M, Schweer KH, Winkler

E. Pharmacokinetics and pharmacodynamics as

well as metabolism following orally and intrave-

nously administered 14C glipizide, a new anti-

161

FABAD J. Pharm. Sci., 31, 151-161, 2006

diabetic, Diabetologia, (Suppl) 9, 320-330, 1973.

84. Pentikainen PJ, Neuvonen PJ, Penttila A. Pharma-

cokinetics and pharmacodynamics of glipizide in

healthy volunteers, Int J Pharmacol Ther, 21, 98-

107, 1983.

85. Huupponen R, Seppala P, Lisalo E. Glipizide

pharmacokinetics and response to diabetics, Int

J Pharmacol Ther Toxicol, 20, 417-422, 1982.

86. Kannisto H, Neuvonen PJ. Adsorption of sulfony-

lureas onto activated charcoal in vitro, J Pharm

Sci, 73, 253-256, 1984.

87. Elvander-Stahl E, Melander A, Wahlin-Boll E.

Indobufen interacts with the sulphonylurea, glip-

izide, but not with the _-adrenergic receptor an-

tagonists, propranolol and atenolol, Br J Clin

Pharmacol, 18, 773-778, 1984.

88. Defang O, Shufang N, Wei L, Hong G, Hui L,

Weisan P. In vitro and in vivo evaluation of two

extended release preparations of combination

metformin and glipizide, Drug Dev Ind Pharm, 31,

677-685, 2005.

89. Balant L, Fabre J, Zahn GR. Comparison of phar-

macokinetics of glipizide and glibenclamide in

man, Eur J Clin Pharmacol, l 8, 63-69, 1975.

90. Fuccella LM, Tamassia V, Valzelli G. Metabolism

and kinetics of the hypoglycemic agent glipizide

in man - comparison with glibenclamide, J Clin

Pharmacol, 13, 68-75, 1973.

91. Goldaniga MC, Pianezzola E, Valzelli G, Amborgi

V. Metabolism of glipizide in the rat and dog and

its tissue distribution in the mouse, Arzneim Forsch,

23, 242-247, 1973.

92. Verma KR, Grag S. Development and evaluation

of osmotically controlled oral drug delivery system

of glipizide, Eur J Pharm Biopharm, 57, 513-525,

2004.