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Vol 2 Issue 2 Jul –Dec 2011 76-80. Print ISSN – 2229 7502
Bioavailability studies of Pioglitazone with Antacid –
An Invivo Evaluation in Human Volunteers
S.Thirumurugu1*, V.Parthasarathy1, D.C.Arumainayagam2, and
1Department of Pharmacy, Annamalai University, Annamalai nagar, Tamilnadu, 2Department of Medicine, Rajah Muthiah Medical College & Hospital, Annamalai University, Annamalai nagar, Tamilnadu, India- 608002. ABSTRACT:
The intestinal absorption of oral-anti diabetic drugs in the treatment of type-II diabetes mellitus is altered when they are concomitantly administered with antacids, and other antinuclear drugs, antibiotics
and others. A randomized cross over study in two phases and a washout period of 4 weeks was carried out
to evaluate the bioavailability of anti diabetic drug pioglitazone when used with Digene Gel (Magnesium
Hydroxide, Simethicone, Aluminium Hydroxide), a drug for management of problems in gastrointestinal
tract.The study has been approved by the institutional ethical committee of Raja muthiah medical college
and Hospital, Annamalai University. In the present study 10 diabetic patients received Digene Gel (10 ml)
for 5 days. After overnight fasting on 6th day a single dose of pioglitazone (30mg) was given. The blood
samples following the intake were taken at different time intervals of 1, 2, 3, 4, 5, 7, 9 and 12 hours. The
plasma samples (100µl) were injected into HPLC system after separation. The mobile phase comprised of
Methanol: acetonitrile: mixed phosphate buffer (pH 2.6) at a ratio of (40:12:48). Analyses were run using
C18 column (4.6 mm × 250 mm, 100 A) Luna. PHENOMINEX, USA was set at 30 C at a flow rate of
1.2 ml.min-1 with UV detector operating at a detection wave length of 269nm in HPLC and the
pharmacokinetic parameters were calculated by using the software Kinetica (Version 4.4.1Innaphase,
USA). The study reveals that the absorption of pioglitazone was delayed when it was concomitantly
administered with Digene Gel.
Keywords: Bioavailability, Anti diabetic drugs, Pioglitazone, Digene Gel, Pharmacokinetics, Concomitant
administration, Drug interaction.
The term diabetes mellitus describes a suffering from diabetes and expected to rise 69.9 metabolic disorder of multiple etiologies million by 2025 [21]. Chronic elevation of blood characterized by chronic hyperglycemia with glucose levels leads to many co-existing disturbances of carbohydrate, fat and protein complications like diabetic retinopathy, diabetic metabolism resulting from defects in insulin neuropathy, peptic ulcer, diabetic foot ulcer. secretion, insulin action, or both [1]. Currently Drug therapy in Type II diabetes becomes more diabetic mellitus is a great threat to the world complex as many individuals are on multiple community with more than 100 million persons drug therapy and administer many drugs during suffering from diabetes. The prevalence and the same period of time to treat secondary incidence of diabetes is increasing in most diabetic complications [3, 11, 13, and 16]. A populations, being more prominent in developing closer monitoring and supervision of drug countries as follows, in USA more than 16 therapy is required so that drug related problems million, in republic of China more than 14 can be prevented or detected at an early stage. million, in Africa more than 20 million. India An increasing number of drug related problems leads the world largest number diabetic subjects are caused by drug inter actions. [3, 12-16]. and is being termed the "diabetes capital of the Currently clinicians come across the problem of world ". With 40.9 million people currently erratic absorption of oral anti diabetic drugs Corresponding Author:- S.Thirumurugu Email: [email protected]
International Journal of Preclinical and Pharmaceutical Research
Vol 2 Issue 2 Jul –Dec 2011 76-80. Print ISSN – 2229 7502
when administered with other drugs prescribed for co- for 5 days. After an overnight fast on day 6 a single dose of existing diseases. Due to this, bioavailability of oral anti Pioglitazone (PIOGLIT 30mg) was administered orally with diabetic drugs is altered. Pioglitazone is a thiozolidinedione 150ml of water [2]. Volunteers received a standard meal 3h compound used in the treatment type II diabetes. It is an after dosing. Volunteers received light standard meals 7th h insulin sensitizer that acts as agonist of the preoxsome and 11th h after dosing. (PPAR - γ) [5, 8]. The main active metabolites are M – IV (a hydroxyl derivatives) and M – III (a ketone derivatives); 2.4. PHARMACOKINETICS OF PIOGLITAZONE
the latter being formed from M –IV (Figure 1) [9]. Another metabolite M – II also has pharmacological activity, but it administered of Pioglitozone by orally at 1, 2, 3, 4, 5, 7, 9, concentrations are low and it does not significantly 12 later through median capital vein, and collected in EDTA contribute to the total amount of active species. The treated vacationers tubes. Blood samples were immediately circulating concentrations of the metabolites M - IV and M - centrifuged at 5000rpm for 10 min to obtain plasma and III are equal to or greater than those of the parent stored at -20°C until analysis. Pioglitazone concentration Pioglitazone and they have considerably longer half-life was determined by addition of 100µl acetonitrile with 100µl than Pioglitazone [2]. In vitro studies suggested that of plasma to deprotinise the proteins. The mixture was pioglitazone is metabolized by several cytochrome P450 vortex mixed for 5 min after which it was centrifuged at (CYP) enzymes but mainly by CYP2C8 and CYP3A4 [5, 10000rpm for 10 min.100µl of supernatant liquid was 8]. The study will ensure that, if it shows no effect on injected into the HPLC system for analysis [5.9] .The UV pharmacokinetics of pioglitazone, it can be co-administered detector was set at 269 nm for the present analysis. C18 for the better management of problems occurs in column (4.6 mm × 250 mm, 100 A) Luna. PHENOMINEX, gastrointestinal tract as co-existing diseases of type II USA was set at 30 C. The mobile phase comprised of Methanol: acetonitrile: mixed phosphate buffer (pH 2.6) at a ratio of (40:12:48) at a flow rate of 1.2 ml.min-1[3]. Materials and Methods
2.1. Materials
2.5. Pharmacokinetic analysis
The standard drug pioglitazone was received as gift Peak plasma concentration (Cmax), Time to Cmax (tmax), AUC sample from Paris Dakner Microspheres (P) Ltd, Chennai, from 0 to 12h (AUC0-12), t½. All the pharmacokinetic and India. The test drugs were Pioglitazone 30 mg tablets statistical data were calculated by using the software (PIOGLIT), Cipla, and Digene Gel 10 ml, Abbott India Kinetic, (Version 4.4.1, Innaphase, USA). Limited. All other chemicals were used of analytical grade. Freshly double distilled deionised water, filtered through Results and discussion
0.2µm nylon filter (47 mm) in Millipore unit (USA), was Currently the management of type II diabetes used throughout the experiments. The drug analysis was becoming more complex since the recommended global carried out using HPLC system (Shimaddzu LC -10 AD) approach of combination drug therapy has increased the risk having gradient pump (LC 10 AD UP) Rheodyne injector of pharmacokinetics interactions in patients with diabetes port, and UV/Vis detector (SPD 10A VP). The data [21]. The activity of one drug could alter the interpretation was done with Shimadzu system controller pharmacokinetics of another drug and it may be due to risk (SCL – 10 AVP). of the enzyme inverse reaction upon the plasma levels of concomitantly administered drugs [22]. Pioglitazone is 2.2 Subjects
rapidly absorbed in GIT, its oral bioavailability exceeds Ten diabetic patients (men age range from (21-30) 80%, and it is extensively metabolized by hydroxylation and weight range (57-79kg) participated in the study after oxidation to form active and inactive metabolites in the liver obtaining a written informed consent and were ascertained [23]. In vivo studies suggest that the drug is metabolized by to be healthy by medical history Clinical examination and several cytochrome P450 (CYP) enzymes, but mainly by routine laboratory tests. No one even on medication. Study CYP2C8 and CYP3A4 [22]. The main active metabolites of protocol was approved by ethics committee for studies in Pioglitazone are M-IV (a hydroxyl derivative) and M-III (a healthy subjects and primary care of the Rajah Muthiah ketone derivative). The M-III being formed from M-IV Medical College and hospital, Chidambaram. (Figure 1). The circulating concentrations of the metabolites M-IV and M-III are equal to or greater than those of the 2.3. Study design
parent Pioglitazone and they have considerably longer half- A randomized cross over study with two phases lives than Pioglitazone [2] .The Digene Gel (Each 10 ml and a washout period of 4weeks was carried out. Volunteers contains Magnesium hydroxide IP 185 mg, Simethicone IP took 10ml of Digene Gel orally once daily at 20.00 h (8 am) 50 mg, Dried Aluminium hydroxide Gel IP 830 mg) . International Journal of Preclinical and Pharmaceutical Research

Vol 2 Issue 2 Jul –Dec 2011 76-80. Print ISSN – 2229 7502
The effect of Digene Gel on the pharmacokinetics of
3). The study has been carried out with five volunteers. Pioglitazone was assessed using a randomized, two cross Antacid delays the absorption of Pioglitazone and alters tmax. over study with wash out period of 4 weeks. Volunteers There is no interaction in metabolism of Pioglitazone. took 1o ml of Digene Gel orally once daily at 20.00 hrs Physiologic factors like pH of GIT, Gastric emptying time, (8pm) for 5 days. After an overnight fasting on 6 day at 9.00 intestinal transit time, and body posture, emotional status am single dose of 30mg Pioglitazone (PIOGLIT) was etc., to be discussed and conformed. Hence the absorption administered orally with 150ml of water. The blood samples of Pioglitazone delayed by the concomitant administration were drawn before and after administration of Pioglitazone. of Digene Gel and may produce hyperglycemia in the The separated plasma was analyzed in HPLC system. The systemic circulation. It may lead to the increasement of data obtained from the analysis shows that of Digene Gel other complications like adverse reaction and toxicity of delays the absorption of Pioglitazone due to that increases the Cmax, AUC and t½ of Pioglitazone after 2hrs (Figure 2 &
The metabolism of pioglitazone in humans [9]. The metabolite M-XI is a previously unrecognized metabolite. The image
Courtesy: Tiina Jaakkola, et al., Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central
Hospital, Helsinki, Finland
International Journal of Preclinical and Pharmaceutical Research
Vol 2 Issue 2 Jul –Dec 2011 76-80. Print ISSN – 2229 7502
Plasma concentration time curve of pioglitazone alone Plasma concentration time curve of pioglitazone concomitantly administred with Antacid Plasma Concentration – time curve of Pioglitazone after its Plasma Concentration time curve of Pioglitazone after its oral administration (30mg) with Digene Gel (10ml) in pre- oral administration (30mg) in human volunteers. The treated human volunteers. The experiments were carried out experiments were carried out by using by the plasma by using by the plasma samples of diabetic patients. Each samples of diabetic patients. Each point represents the mean point represents the mean ± standard deviation (n=10) ± standard deviation (n=10)
Table. 1 Pharmacokinetic parameters of Pioglitazone inAntacid pretreated human volunteers
Pharmacokinetics parameter
Pioglitazone alone
Pioglitazone with Antacid
AUC0-t (ng *h/mL) 382.0.13±18.483 Volunteers took 30mg Pioglitazone (PIOGLIT) orally once daily for 5 days. After an overnight fast on the day 6 a single dose of 10ml of Digene Gel was administered orally there after pharmacokinetics of Pioglitazone was carried out. Tmax - Time to Reach; Cmax - Peak Plasma Concentration; AUC - Area Under the Plasma Concentration Curve; t1/2 - Half Life. CONCLUSION
activity by CYP3A4 mediated inhibition. This finding The present study was carried out with an attempt indicates that Digene Gel delays the absorption of to investigate any possible interaction occurs between pioglitazone during absorption phase. There is no inter Digene Gel and Pioglitazone in the treatment of Type II individual variation in AUC of Pioglitazone from 0–12 hrs diabetes with the problems of gastrointestinal tract. The as compared to standard phase (pioglitazone alone). The increase in tmax and t1/2 of Pioglitazone was found to be chromatograms. Digene Gel was found to delay the higher when it is co-administered administered with Digene absorption of pioglitazone upto 4 hrs. From 2 hr onwards as Gel and it may increase the blood glucose lowering efficacy compared to standard phase (pioglitazone alone), decreases of Pioglitazone. This may lead to accumulation of drug in elimination rate (t½) of pioglitazone in plasma (Table 1) and the body, which may lead to toxicity. Therefore, it is also revealed that Cmax of pioglitazone was not affected advisable to monitor blood glucose level when starting the much. It clarifies that there is no change in the intestinal therapy with Digene Gel to adjust the required dosage of microsomal activity but changes the hepatic microsomal International Journal of Preclinical and Pharmaceutical Research
Vol 2 Issue 2 Jul –Dec 2011 76-80. Print ISSN – 2229 7502
In conclusion, the present study suggests that substantial increase in plasma concentration of pioglitazone Digene Gel delays the concentration of pioglitazone causes and it may lead the risk of toxicity in diabetic patients.
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