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DRUG INTERACTIONS

Multiple-Dose Administration of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, Does Not Alter the Single-Dose Pharmacokinetics of Rosiglitazone in Healthy Subjects

Goutam C. Mistry, MSc, Arthur J. Bergman, PhD, Wen-Lin Luo, PhD, Caroline Cilissen, MSc, Wouter Haazen, MD, Michael J. Davies, PhD, Keith M. Gottesdiener, MD, FACP, John A. Wagner, MD, PhD and Gary A. Herman, MD

From Merck & Co, Inc, Whitehouse Station, New Jersey (Mr Mistry, Dr Bergman, Dr Luo, Dr Davies, Dr Gottesdiener, Dr Wagner, Dr Herman); Merck & Co, Inc, Brussels, Belgium (Ms Cilissen); and SGS Life Sciences Services, Antwerp, Belgium (Dr Haazen).

Address for reprints: Address for correspondence: Gary A. Herman, MD, Merck Research Laboratories, Mail Code RY34-A536, PO Box 2000, Rahway, NJ 07065-0900.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of type 2 diabetes. Sitagliptin is mainly renally eliminated and not a potent inhibitor of CYP450 enzymes in vitro. Rosiglitazone, a thiazolidenedione, is an insulin sensitizer and mainly metabolized by CYP2C8. Since both agents may potentially be coadministered, the purpose of this study was to examine the effects of sitagliptin on rosiglitazone pharmacokinetics. In this open-label, randomized, 2-period, crossover study, 12 healthy normoglycemic subjects, 21 to 44 years, received single 4-mg doses of rosiglitazone alone in one period and coadministered with sitagliptin on day 5 following a multiple-dose regimen for sitagliptin (200 mg once daily x 5 days) in the other period. The geometric mean ratios and 90% confidence intervals ([rosiglitazone + sitagliptin]/rosiglitazone) for rosiglitazone AUC0-{infty} and Cmax were 0.98 (0.93, 1.02) and 0.99 (0.88, 1.12), respectively. In conclusion, sitagliptin did not alter the pharmacokinetics of rosiglitazone in healthy subjects.

Key Words: MK-0431 • sitagliptin • DPP-4 • pharmacokinetics • rosiglitazone

Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a new potential therapeutic approach to treat type 2 diabetes.1 DPP-4 inhibitors are considered incretin enhancers by inhibiting the enzymatic degradation of incretins, particularly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptides (GIP) that stimulate insulin production and release and suppress glucagon release in a glucose-dependent manner.1-4 Sitagliptin is an oral, potent, and highly selective DPP-4 inhibitor indicated for the treatment of type 2 diabetes.5 Sitagliptin inhibited DPP-4 activity, elevated active GLP-1 levels, and markedly reduced glucose levels following an oral dextrose challenge in animal models.6 In healthy volunteers, single and multiple doses of sitagliptin dose dependently inhibited plasma DPP-4 activity and augmented intact (active) GLP-1 levels.7,8 Plasma concentrations of sitagliptin generally reach steady state after 3 days of dosing,8 and the systemic exposure, as measured by the area under the curve (AUC), increases dose proportionally with increasing dose.7,8 Sitagliptin is renally eliminated, and the apparent terminal half-life of the 100-mg clinical dose of sitagliptin is approximately 12 hours.7,8 The absolute bioavailability of sitagliptin is 87%, with food having no effect on the pharmacokinetics of sitagliptin.7 Sitagliptin does not inhibit CYP enzymes in vitro.9 In other drug interaction studies, sitagliptin has not had clinically meaningful effects on simvastatin, warfarin, metformin, glyburide, and oral contraceptives.9,10

Rosiglitazone, a peroxisome proliferator-activated receptor {gamma}, has been shown to improve hepatic and peripheral sensitivity to insulin.11 Rosiglitazone is used as monotherapy or in combination with other agents such as sulfonylureas or metformin to reduce elevated blood glucose levels for the management of type 2 diabetes.12,13 Because of their unique mechanisms of action, there is a potential for sitagliptin and rosiglitazone to be coadministered in patients with type 2 diabetes. Thus, it is of interest to evaluate potential drug-drug interactions between these agents. Rosiglitazone and sitagliptin are metabolized by different mechanisms. The hepatic metabolism of rosiglitazone is predominantly mediated by CYP2C8, with CYP2C9 contributing as a minor pathway.14,15 This open-label, 2-period, crossover study was designed to measure the effect of steady-state concentrations of sitagliptin (achieved by 5 days of once-daily dosing) on single-dose pharmacokinetics of rosiglitazone in healthy subjects. Since sitagliptin is predominantly renally excreted as unchanged drug,7 the present study evaluated only the effects of sitagliptin on rosiglitazone pharmacokinetics and not vice versa.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
The study was conducted in 12 healthy male and female subjects of nonreproductive potential with normal glucose levels, 18 to 45 years of age, weighing between 60 and 95 kg, who were considered generally in good health by the investigator on the basis of medical history and physical examination including vital signs, 12-lead electrocardiogram (ECG), and routine laboratory testing (hematology/blood chemistry/urinalysis). Furthermore, unless allowed by the investigator for minor ailments, the subjects were not permitted to take any prescription or nonprescription medications within 14 days of the start of dosing and throughout the study.

Study Design
This was an open-label, randomized, single center, 2-period, crossover study. The subjects were randomized to receive 2 treatment regimens according to a computer-generated allocation schedule as follows: a single oral 4-mg dose of rosiglitazone (Avandia, two 2-mg capsules; GlaxoSmithKline, Collegeville, Penn) in the fasted state or sitagliptin 200 mg once daily on days 1 to 5 (totaling 5 doses) with a single oral 4-mg dose of rosiglitazone coadministered with sitagliptin on day 5. Administration of all study drug was with 240 mL of water following an overnight fast on day 1 in the period when a single oral 4-mg dose of rosiglitazone was administered alone and on day 5 in the period when rosiglitazone was coadministered with sitagliptin. However, on days 1 to 4 in the period when rosiglitazone was coadministered with sitagliptin, sitagliptin was administered without regard to food. The administration of all study drugs was witnessed by the medical staff at the clinical research unit. Rosiglitazone was administered at the same clock time in each period. The subjects were sequestered at the research unit on the pharmacokinetic sampling days; however, on all other study days, they were discharged after dosing. Both periods were separated by a washout interval of at least 7 days before crossing over to the other treatment regimen.

Safety assessments included a physical examination, 12-lead ECG, vital signs at rest (systolic/diastolic blood pressure, pulse rate, respiratory rate, body temperature), and routine laboratory tests (hematology/blood chemistry/urinalysis), which were performed at prestudy (screening), before the first dose (day 1) in the first period only, at 24 hours postdose on day 1 of the rosiglitazone-only period and day 5 of the coadministration period (laboratory testing and vital signs only), and at the post-study visit, which occurred approximately 14 days after administration of the last dose of the study drug. Clinical adverse experiences were also monitored throughout the study from the prestudy (screening) to the poststudy visit.

This study was conducted at SGS Life Sciences Services (Antwerp, Belgium) according to the provisions of the Declaration of Helsinki, and written informed consent was obtained from each subject prior to conducting any protocol-related procedure. The study was approved by the independent ethics review committee (Commissie voor Medische Ethiek, Antwerp, Belgium).

Pharmacokinetic Assessments
Blood samples for rosiglitazone assay were collected at the following time points over a 24-hour period after rosiglitazone administration on day 1, in the period when administered alone, and day 5 in the period when coadministered with sitagliptin: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours. At each collection, 3 mL of blood were drawn into one 3-mL EDTA (spray-dried) lavendar top Vacutainer tube. The tubes were placed on ice immediately after collection and then centrifuged at 3000 rpm for 15 minutes at 4°C. The plasma was then transferred to 4.5-mL polypropylene NUNC tubes and stored in a freezer at -20°C until analysis. The NUNC tubes were sent to Covance Bioanalytical Services LCC on dry ice for drug assay.

Plasma samples were assayed for rosiglitazone concentrations using high-performance liquid chromatography (Allure PFP Propyl 5 µm, 2.1 mm x 50 mm column) with tandem mass spectroscopy (MS/MS) detection. Analyte and internal standard (rosiglitazoned4) were detected by MS/MS using multiple reaction monitoring (MRM) with electrospray interface in the positive ion mode. The MS transitions monitored were 358.1 -> 135.1 m/z for rosiglitazone and 362.5 -> 135.1 m/z for the internal standard. The lower limit of quantification for rosiglitazone was 2.00 ng/mL, with an assay linear calibration range of 2.00 to 1000 ng/mL. Accuracy and precision of the rosiglitazone plasma assay were determined using 3 sets of rosiglitazone calibration standards tested at 9 different concentrations over the calibration range. The mean assay value was within 1% of the theoretical value for each of the 9 concentrations. Furthermore, the coefficient of variation of these values was less than 2.3% for each concentration.

Plasma concentrations and actual sampling times relative to dose were used to determine pharmacokinetic parameters (with the exception of Tmax) for each subject. The onset of the apparent terminal log-linear portions of the individual plasma concentration-time profiles was determined by inspection. The apparent terminal rate constant ({lambda}) was estimated by regression of the terminal log-linear portion of the plasma concentration-time profile; t1/2 was calculated as the quotient of ln (2) and {lambda}. AUC to the last time point was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. AUC0-{infty} was estimated as the sum of AUC to the last measured concentration and the extrapolated area given by the quotient of the last measured concentration and {lambda}. Cmax and Tmax were obtained by inspection of the plasma concentration data. Provided that the actual observed time of Tmax did not differ in a meaningful way from the nominal plasma sampling time, nominal plasma sampling times were used to determine Tmax. WinNonLin version 5 was used in the pharmacokinetic computations for this study.

Statistical Analysis
The effect of 200-mg once-daily multiple-dose administration of sitagliptin for 5 days on the 4-mg single-dose rosiglitazone pharmacokinetic parameters (AUC0-{infty}, Cmax, Tmax, and apparent t1/2) was evaluated using an analysis of variance (ANOVA) model appropriate for a 2-period, crossover design with terms sequence, subject within sequence, period, and treatment. Appropriate transformations on the pharmacokinetic parameters were used (ie, log transformation for AUC0-{infty} and Cmax, rank for Tmax, and inverse for apparent t1/2). Back-transformed summary statistics and inferential results were reported for pharmacokinetic parameters of rosiglitazone in the presence and absence of sitagliptin. The normality assumption of the model was examined graphically and tested by using the Shapiro-Wilk statistic.

Since thiazolidenediones are transcriptional regulators, overall drug exposure (ie, AUC) was considered to be the most relevant pharmacokinetic parameter for this study. A 90% confidence interval (CI), based on the t distribution, was generated from the above ANOVA model for the AUC0-{infty} geometric mean ratio (GMR; rosiglitazone + sitagliptin/rosiglitazone). Although the 90% CI of (0.80-1.25) is sometimes chosen for drug interaction studies,16 given the potential for dose-related adverse experiences with rosiglitazone (eg, edema and weight gain), a wider GMR for AUC0-{infty} (with vs without sitagliptin) of greater than 1.43 was considered potentially clinically meaningful. For instance, while 8 mg is considered to be a generally well-tolerated dose of rosiglitazone, 12 mg (ie, 50% higher) is not. Depending on the starting dose, reductions in exposure (ie, a GMR of less than or equal to 0.7) may be less efficacious than deemed. Thus, the 90% CI was compared to the prespecified bounds of [0.70, 1.43]. If the 90% CI for the rosiglitazone AUC0-{infty} GMR (rosiglitazone + sitagliptin/rosiglitazone) was contained within the interval [0.70, 1.43], it was concluded that the coadministration of 200-mg once-daily multiple doses of sitagliptin for 5 days did not alter the 4-mg single-dose pharmacokinetics of rosiglitazone in healthy subjects.

For the power calculation, if the true AUC(0-{infty}) GMR (rosiglitazone + sitagliptin/rosiglitazone) is 1.00, then a sample size of n = 12 subjects provided this study with a greater than 99% probability of observing the 90% CI for the GMR within [0.70, 1.43]. If the true AUC(0-{infty}) GMR is between 0.84 to 1.19, then a sample size of n = 12 subjects provided this study with at least 80% probability that the 90% CI for this comparison is between [0.70, 1.43]. These calculations were based on a pooled within subject standard deviation for AUC(0-{infty}) of 0.1655 ln ng•h/mL.17,18


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Demographics
All 12 subjects, 8 male and 4 female subjects, completed the study. The subjects had a mean age of 34.4 years (actual range, 21-44 years), mean weight of 74.5 kg (actual range, 61.1-88.4 kg), and mean height of 170.5 cm (actual range, 156.0-182.5 cm).

Effect of Sitagliptin on Rosiglitazone Pharmacokinetics
The mean rosiglitazone plasma concentration-time profiles with and without sitagliptin are shown in Figure 1, and the mean pharmacokinetic parameters are provided in Table I. The rosiglitazone AUC0-{infty} GMR (rosiglitazone + sitagliptin/rosiglitazone) was 0.98 (Table I), and the corresponding 90% CI of (0.93, 1.02) was within the prespecified bounds of (0.70, 1.43), indicating that sitagliptin did not alter the plasma pharmacokinetic profile of rosiglitazone. Inspection of the 90% CI of Cmax GMR (0.99 [CI, 0.88, 1.12]) suggested that the single-dose administration of rosiglitazone with sitagliptin at steady state did not alter the rosiglitazone Cmax. In addition, the coadministration of rosiglitazone with sitagliptin did not change the Tmax (P = .782) or apparent t1/2 (P = .104) of rosiglitazone.


Figure 1
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  		Figure 1. Mean (standard deviation) plasma concentration-time profiles following single 4-mg doses of rosiglitazone with or without multiple 200-mg doses of sitagliptin (N = 12).

 

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  		Table I Mean Pharmacokinetic Parameters Following Single 4-mg Doses of Rosiglitazone With or Without Multiple 200-mg Doses of Sitagliptin

 

Safety and Tolerability
Sitagliptin and rosiglitazone were generally well tolerated whether administered alone or together. No serious adverse experiences were reported, and no subject discontinued the study because of an adverse experience. Seven (7) of the 12 subjects reported a total of 19 nonserious clinical adverse experiences. Of these, the following 10 adverse experiences were considered by the investigator to be possibly drug related: 6 reports of headache, of which 2 were reported after sitagliptin was administered alone, 2 were reported after rosiglitazone was administered alone, and 2 were reported when both drugs were coadministered; 2 reports of nausea and 1 report of vomiting also after both drugs were coadministered; and feeling warm, which was reported after sitagliptin was administered alone. The other 9 adverse experiences were not considered by the investigator to be drug related. All of the adverse experiences were transient and judged to be mild in intensity. No laboratory adverse experiences, including hypoglycemia, or treatment-related clinically meaningful deviations in physical examinations, vital signs, and ECG parameters occurred during the study.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Sitagliptin belongs to a new class of antihyperglycemic drugs known as DPP-4 inhibitors.5 Many patients with type 2 diabetes do not achieve glycemic treatment targets with monotherapy, and thus, combination therapy is necessary. There is a potential that sitagliptin will be coadministered with the thiazolidenedione class of oral antihyperglycemic agents such as rosiglitazone. Therefore, drug-drug interactions need to be evaluated for any potential drug combinations. In this study, healthy subjects were chosen to eliminate concomitant medications that might confound an assessment of the effect of sitagliptin on rosiglitazone pharmacokinetics. Since sitagliptin is mainly renally eliminated7 and rosiglitazone is predominantly metabolized by CYP2C8 and CYP2C9,14,15 effects of rosiglitazone on sitagliptin pharmacokinetics were not expected and thus were not examined in the present study. Only the effects of sitagliptin at steady state concentrations on the single-dose pharmacokinetics of rosiglitazone were investigated in this study. In addition, since rosiglitazone is a CYP2C8 substrate, this study also assessed the potential in vivo inhibitory effects of sitagliptin on CYP2C8-mediated elimination. Rosiglitazone was chosen as an appropriate probe substrate for CYP2C8 metabolism since previous studies have demonstrated inhibition of the CYP2C8-mediated metabolism of rosiglitazone in vivo.19,20 The dose of rosiglitazone chosen, 4 mg, is the recommended and lowest starting clinical dose13 that was anticipated to provide sufficiently high plasma drug levels and provide the maximum sensitivity in which to fully assess any potential interactions. Furthermore, the 200-mg dose of sitagliptin, which is twice the clinical dose, was also chosen to maximize the sensitivity for detecting an impact on rosiglitazone pharmacokinetics.

The results of this study indicated that steady-state concentrations of sitagliptin (obtained after 5 days of administration of once-daily dosing) had no effect on the pharmacokinetics of a single dose of rosiglitazone. The AUC0-{infty} GMR (rosiglitazone + sitagliptin/rosiglitazone) was 0.98, with a corresponding 90% CI of (0.93, 1.02), which was contained within the prespecified bounds of (0.70, 1.43) and supported the study's primary hypothesis. The Cmax GMR (rosiglitazone + sitagliptin/rosiglitazone) was 0.99, with a corresponding 90% CI of (0.88, 1.12). In addition, Tmax and apparent t1/2 were similar across treatments, and there were no statistically significant differences between treatments. These results are in agreement with the findings that sitagliptin was not a potent inhibitor of CYP enzymes in vitro (IC50 >100 µM for CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6).9 Furthermore, the results of this study also indicated that sitagliptin was not a potent inhibitor of CYP2C8 metabolism in vivo. These findings indicated that sitagliptin could be administered with rosiglitazone without concern for altering the plasma concentrations of the CYP2C8 substrate and that no dosage adjustment is necessary. Based on pharmacokinetic considerations, the data from this study tend to suggest that other drugs also predominantly metabolized by CYP2C8, such as repaglinide, paclitaxel, amodiaquine, and torosemide, could possibly be coadministered with sitagliptin without warranting any dose adjustment. Another commonly administered drug of the thiazolidenedione class is pioglitazone. Since pioglitazone metabolism also predominantly involves CYP2C8 and, to a lesser degree, CYP3A4,21 a pharmacokinetic interaction with sitagliptin, although not yet investigated, would not be expected since it has demonstrated that sitagliptin is also not an inhibitor of CYP3A4.22

Multiple-dose administration of sitagliptin with a single dose of rosiglitazone was also generally well tolerated in the healthy subjects in this study. There were no serious adverse experiences or laboratory adverse experiences, and all nonserious clinical adverse experiences were transient and mild in intensity and did not require dose interruption or adjustment.

In conclusion, sitagliptin did not alter the pharmacokinetics of rosiglitazone in healthy subjects. Since the pharmacokinetics of sitagliptin in patients with type 2 diabetes is highly similar to that of healthy subjects,7,8,23 it is anticipated that the pharmacokinetics of rosiglitazone will not be altered when coadministered with sitagliptin in patients with type 2 diabetes.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
Financial disclosure: This study was funded by Merck & Co, Inc.

DOI: 10.1177/0091270006297007


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Ahren B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3: 365-372.[Medline] [Order article via Infotrieve]

2. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26: 2929-2940.[Abstract/Free Full Text]

3. Sorbera LA, Revel L, Castaner J. P32/98: antidiabetic dipeptidyl-peptidase IV inhibitor. Drugs Future. 2001;26: 859-864.[CrossRef]

4. Villhauer EB, Coppola GM, Hughes TE. DPP-IV inhibition and therapeutic potential. Ann Rep Med Chem. 2001;36: 191-200.

5. Januvia (sitagliptin phosphate) [product circular]. Whitehouse Station, NJ: Merck & Co, Inc; 2006.

6. Kim D, Wang L, Beconi M, et al. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005;48: 141-151.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

7. Herman GA, Stevens C, Van Dyck K, et al. Pharmacokinetics and pharmacodynamics of single doses of sitagliptin, an inhibitor of dipeptidyl peptidase-IV, in healthy subjects. Clin Pharmacol Ther. 2005;78: 675-688.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

8. Bergman AJ, Stevens C, Zhou YY, et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006;28: 55-72.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Herman G, Bergman A, Wagner JA. Sitagliptin, a DPP-4 inhibitor: an overview of the pharmacokinetic (PK) profile and the propensity for drug-drug interactions (DDI)(abstract). Diabetologia. 2006; 49(suppl 1): 481-482.

10. Herman GA, Bergman A, Yi B, Kipnes M, for the Sitagliptin Study 012 Group. Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes. Curr Med Res Opin. 2006;22: 1939-1947.

11. St John Sutton M, Rendell M, Dandona P, et al. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care. 2002;25: 2058-2064.[Abstract/Free Full Text]

12. Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs. 2005;65: 385-411.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

13. Cox SL. Rosiglitazone maleate/metformin hydrochloride: a new formulation therapy for type 2 diabetes. Drugs Today (Barc). 2004;40: 633-643.

14. Baldwin SJ, Clarke SE, Chenery RJ. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol. 1999;48: 424-432.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Cox PJ, Ryan DA, Hollis FJ, et al. Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans. Drug Metab Dispos. 2000;28: 772-780.[Abstract/Free Full Text]

16. Huang S-M, Lesko LJ, Williams RL. Assessment of the quality and quantity of drug-drug interaction studies in recent NDA submissions: study design and data analysis issues. J Clin Pharmacol. 1999;39: 1006-1014.[Abstract]

17. Miller AK, DiCicco RA, Freed MI. The effect of ranitidine on the pharmacokinetics of rosiglitazone in healthy adult male volunteers. Clin Ther. 2002;24: 1062-1071.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

18. Miller AK, Inglis AM, Culkin KT, et al. The effect of acarbose on the pharmacokinetics of rosiglitazone. Eur J Clin Pharmacol. 2001;57: 105-109.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

19. Hruska MW, Amico JA, Langaee TY, et al. The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects. Br J Clin Pharmacol. 2005;59: 70-79.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

20. Niemi M, Backman JT, Granfors M, et al. Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia. 2003;46: 1319-1323.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

21. Kirchheiner J, Roots I, Goldammer M, et al. Effect of genetic polymorphisms in cyctochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin Pharmacokinet. 2005;44: 1209-1225.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

22. Bergman AJ, Cote J, Maes A, et al. Sitagliptin (MK-0431), a selective dipeptidyl-peptidase-IV (DPP-IV) inhibitor, does not affect the pharmacokinetics of simvastatin in humans [abstract]. Clin Pharm Ther. 2006;79(2 suppl): S48.

23. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels following an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006; 91: 4612-4619.[Abstract/Free Full Text]
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D. Q. Pham, A. Nogid, and R. Plakogiannis
Sitagliptin: A novel agent for the management of type 2 diabetes mellitus
Am. J. Health Syst. Pharm., March 15, 2008; 65(6): 521 - 531.
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