Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative ring opening of troglitazone (TGZ)(1) a thiazolidine 2,4-dione derivative used for the treatment of type II diabetes mellitus, leads to the formation of a quinone metabolite. The formation of TGZ quinone was shown to be NADPH dependent and to require active microsomal enzymes. Quinone formation was not affected by co-incubation with catalase or sodium azide and was partially inhibited (25%) by superoxide dismutase (SOD). Kinetic analysis of TGZ quinone formation in human liver microsomes implied single enzyme involvement. CYP3A isoforms were characterized as the primary enzymes involved in quinone formation by several lines of evidence including: (a) troleandomycin and ketoconazole almost completely inhibited microsomal quinone formation when SOD was present, whereas other CYP inhibitors had minimal effects (<20%); (b) TGZ quinone formation was highly correlated with regard to both contents (r(2): 0.9374) and activities (r(2): 0.7951) of CYP3A4 in human liver microsomes (HLM); (c) baculovirus insect cell-expressed human CYP3A4 was able to catalyze TGZ quinone formation at a higher capacity (V(max)/K(m)) than other human CYPs with the relative contribution of CYP3A4 in HLM estimated to be 20-fold higher than that of other CYPs; (d) TGZ quinone formation was increased by 350% in liver microsomes from rats pretreated with dexamethasone (DEX); and (e) plasma concentrations of TGZ quinone were increased by 260-680% in rats pretreated with DEX. The chemical nature of the quinone metabolite suggests an atypical CYP reaction consistent with a one-electron oxidation mechanism where an intermediate phenoxy radical combines with ferryl oxygen to subsequently form the quinone metabolite.
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PMID:Troglitazone quinone formation catalyzed by human and rat CYP3A: an atypical CYP oxidation reaction. 1138 77

Repaglinide (Prandin), NovoNorm, GlucoNorm, an oral insulin secretagogue, was the first meglitinide analogue to become available for use in patients with type 2 diabetes mellitus. The drug lowers postprandial glucose excursions by targeting early-phase insulin release, an effect thought to be important in reducing long-term cardiovascular complications of diabetes. Repaglinide provided similar overall glycaemic control to that achieved with glibenclamide (glyburide), as assessed by glycosylated haemoglobin (HbA(1c)) and fasting blood glucose levels, and was generally well tolerated in well designed clinical trials. Its rapid onset and relatively short duration of action allow for flexible meal schedules. Two modelled US cost-effectiveness analyses projected lifetime costs and outcomes for a hypothetical cohort of patients with type 2 diabetes. Both analyses projected long-term complications using data on HbA(1c) level changes from short-term clinical trials. Repaglinide plus rosiglitazone was dominant over rosiglitazone in one analysis, and repaglinide plus metformin was dominant over nateglinide plus metformin in the other. A similar Canadian analysis showed a favourable incremental cost-effectiveness ratio (<dollars US 1000 per QALY gained; 2001 values) for patients who switched from a sulphonylurea to repaglinide versus those who remained on sulphonylurea therapy. Long-term outcomes were projected using short-term clinical trial data on postprandial blood glucose level changes in the Canadian study. All three cost-effectiveness analyses are available as abstracts/posters. Two US cost analyses (both published in full) have also been conducted comparing the short-term costs (<or=3 years) of repaglinide, with or without metformin, versus other oral antidiabetic regimens. Results of these analyses are somewhat equivocal because of study design issues and/or a lack of statistically significant differences between treatment groups. In conclusion, repaglinide as monotherapy or in combination with other antidiabetic agents, such as metformin or rosiglitazone, achieves good metabolic control, similar to that achieved with comparable glibenclamide regimens. Severe hypoglycaemic episodes are less common with repaglinide than some sulphonylureas, including glibenclamide. Modelled cost-effectiveness analyses conducted in North America showed favourable results for repaglinide-containing regimens versus comparators, largely attributed to projected reductions in long-term cardiovascular complications using short-term data on changes in glycaemic parameters from clinical trials. Results of these cost-effectiveness analyses (all of which have been published as abstracts/posters) should be interpreted with caution since various assumptions regarding long-term costs and outcomes were necessarily incorporated into the economic models. While repaglinide is a useful addition to the available treatment options in type 2 diabetes, potential long-term advantages versus other agents, such as reducing cardiovascular complications, require confirmation. The prevalence of diabetes mellitus is projected to increase to over 3% of the world's population ( approximate, equals 220 million people) by the year 2010. Globally, 97% of patients with diabetes have type 2 disease, although in industrialised countries the proportion of type 2 disease is about 90%. In 2010, an estimated 14.85 million individuals in the US and 2.88 million in the UK will be diagnosed with type 2 diabetes. In addition, approximately one-third to one-half of individuals with diabetes are unaware that they have the disease, and are therefore undiagnosed. Diabetes is associated with significant morbidity, mortality and economic consequences. For the year 2002 in the US, direct medical costs associated with diabetes (type 1 and 2) were estimated at dollars US 91.8 billion (70% of total costs) and indirect costs at dollars US 39.8 billion (30%), for a total of dollars US 132 billion. Data from more than 7000 patients in eight European countries indicate tha the mean cost per patient with diabetes was dollars US 2928 annually (1999 values), and the proportion of total healthcare expenditure directed toward diabetes ranged from 1.6% to 6.6% depending on the country. Several analyses focusing specifically on type 2 disease showed, not surprisingly, that costs were higher among patients with diabetic complications than in those without complications. Repaglinide, a meglitinide analogue, is an oral insulin secretagogue that reduces postprandial glucose excursions by targeting postprandial insulin release. In clinical trials in patients with type 2 diabetes, repaglinide was usually administered at a dosage of 0.5-4 mg three times daily before meals as monotherapy or in combination with other agents. In placebo-controlled trials of up to 24 weeks' duration in patients with type 2 diabetes, repaglinide achieved statistically significant improvements in glycaemic control, as assessed by glycosylated haemoglobin (HbA(1c)), fasting blood glucose (FBG) and/or postprandial blood glucose (PPBG) levels compared with placebo. Preprandial administration of repaglinide achieved similar glycaemic control to glibenclamide (glyburide) 1.75-15 mg/day and better glycaemic control than glipizide 5-15 mg/day in 1-year, double-blind, randomised trials in patients with type 2 disease, the vast majority of whom had previously received oral antidiabetic therapy. Several randomised, open-label studies have evaluated repaglinide as part of combination therapy over 3-6 months in patients with type 2 diabetes who had inadequate glycaemic control with previous drug therapy. In general, results showed statistically significant improvements in glycaemic control when repaglinide was used in combination with metformin, various thiazolidinediones, or metformin plus bedtime insulin compared with monotherapy with either comparator drug in each study (or metformin plus bedtime insulin in one trial). Other studies in this patient population indicate that metformin plus repaglinide is associated with significantly better glycaemic control than metformin plus nateglinide 60-120 mg three times daily over 16 weeks, and similar glycaemic control to that achieved with metformin in combination with either glibenclamide or glimepiride for up to 1 year. Good glycaemic control has also been achieved with preprandial administration of repaglinide in flexible meal schedules. This was demonstrated in a placebo-controlled trial and in a large, prospective survey of patients receiving repaglinide in a clinical setting. The tolerability profile of repaglinide is characterised by adverse events of mild-to-moderate intensity similar to those associated with sulphonylureas. The most frequently reported adverse events with repaglinide include hypoglycaemia, upper respiratory infection, headache, other respiratory events, musculoskeletal events and gastrointestinal events. Severe episodes of hypoglycaemia are rare with repaglinide and occur approximately 2-2.5 times less frequently than with sulphonylureas. In addition, available data indicate that repaglinide may be less likely to increase bodyweight than various commonly used sulphonylurea agents. In general, repaglinide is also well tolerated when used as part of combination therapy. Repaglinide is metabolised by the cytochrome P450 (CYP) 3A4 enzyme system and therefore has the potential to interact with other CYP3A4 substrates when administered concurrently. A number of studies in healthy volunteers have shown no clinically significant pharmacokinetic drug interactions when repaglinide was administered concomitantly with digoxin, theophylline, warfarin, cimetidine, ketoconazole, rifampicin (rifampin), ethinylestradiol, simvastatin or nifedipine. However, a clinically significant increase in systemic exposure to repaglinide occurs when clarithromycin and repaglinide are administered concurrently, which may necessitate a reduction in repaglinide dosage. Moreover, a potentially hazardous interaction occurs when gemfibrozil (alone or with itraconazole) is used concomitantly with repaglinide. In view of the marked increase in systemic exposure to repaglinide, the combination of repaglinide and gemfibrozil should be avoided if possible. Pharmacoeconomic Analyses of RepaglinideTwo US cost analyses have been conducted with repaglinide in patients with type 2 diabetes (both published in full). One was a retrospective analysis of pharmacy and medical claims data from a large managed care organisation in which costs were adjusted for age, gender and comorbidities. Total adjusted (year 2000) cost per patient over a 9-month period was numerically lower for those treated with a combination of repaglinide plus metformin (dollars US 8924) than for patients who received metformin only (dollars US 9448), metformin plus glibenclamide (dollars US 9576) or repaglinide only (dollars US 11910), although there were no statistically significant differences between treatment groups. The other study, a literature-based decision-tree analysis, projected the proportion of patients achieving a target HbA(1c) level (<7%) and the associated direct medical costs over a 3-year period from the time of diagnosis. Among six different treatment regimens evaluated, costs ranged from dollars US 6106 with glipizide gastrointestinal therapeutic system (GITS) to dollars US 9298 with repaglinide monotherapy (2001/2002 values). Probabilistic sensitivity analysis indicated that first-line therapy with glipizide GITS or metformin would be associated with lower total medical costs than rosiglitazone or repaglinide monotherapy. Three cost-effectiveness analyses, all of which are modelled studies published as abstracts and/or posters, have been conducted with repaglinide in patients with type 2 diabetes. (ABSTRACT TRUNCATED)
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PMID:Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus. 1509 24

The compound, 5-{4-[3-(4-cyclohexyl-2-propylphenoxy)propoxy]phenyl}-1,3-oxazolidine-2,4-dione (compound A) is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. PPARgamma agonists have proven useful in the treatment of type 2 diabetes, which is characterized by hyperglycemia, insulin resistance and/or abnormal insulin secretion. The metabolism of this oxazolidinedione (OZD) was investigated in male rat, dog, monkey and human liver microsomes, and recombinant human cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) in the presence of NADPH. Routes of metabolism included monohydroxylation of the cyclohexane ring at multiple positions, monohydroxylation of the n-propyl side chain or the tether linkage, and OZD ring opening, giving rise to the keto amide and alcohol amide entities. Liver microsomes showed subtle qualitative and quantitative metabolic differences among rat, dog, monkey and human preparations. Further, CYP2C8 and CYP2C19 did not display different regioselectivity for hydroxylation on the cyclohexane ring with both of them giving rise to C-3 and C-4 hydroxy metabolites, but they did display different stereoselectivity with CYP2C8 preferring cyclohexane hydroxylation in equatorial positions and CYP2C19 in axial positions.
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PMID:In vitro metabolism of a new oxazolidinedione hypoglycemic agent utilizing liver microsomes and recombinant human cytochrome P450 enzymes. 1570 77

Type 2 diabetes mellitus affects up to 8% of the adult population in Western countries. Treatment of this disease with oral antidiabetic drugs is characterised by considerable interindividual variability in pharmacokinetics, clinical efficacy and adverse effects. Genetic factors are known to contribute to individual differences in bioavailability, drug transport, metabolism and drug action. Only scarce data exist on the clinical implications of this genetic variability on adverse drug effects or clinical outcomes in patients taking oral antidiabetics. The polymorphic enzyme cytochrome P450 (CYP) 2C9 is the main enzyme catalysing the biotransformation of sulphonylureas. Total oral clearance of all studied sulphonylureas (tolbutamide, glibenclamide [glyburide], glimepiride, glipizide) was only about 20% in persons with the CYP2C9*3/*3 genotype compared with carriers of the wild-type genotype CYP2C9*1/*1, and clearance in the heterozygous carriers was between 50% and 80% of that of the wild-type genotypes. For reasons not completely known, the resulting differences in drug effects were much less pronounced. Nevertheless, CYP2C9 genotype-based dose adjustments may reduce the incidence of adverse effects. The magnitude of how doses might be adjusted can be derived from pharmacokinetic studies. The meglitinide-class drug nateglinide is metabolised by CYP2C9. According to the pharmacokinetic data, moderate dose adjustments based on CYP2C9 genotypes may help in reducing interindividual variability in the antihyperglycaemic effects of nateglinide. Repaglinide is metabolised by CYP2C8 and, according to clinical studies, CYP2C8*3 carriers had higher clearance than carriers of the wild-type genotypes; however, this was not consistent with in vitro data and therefore further studies are needed. CYP2C8*3 is closely linked with CYP2C9*2. CYP2C8 and CYP3A4 are the main enzymes catalysing biotransformation of the thiazolidinediones troglitazone and pioglitazone, whereas rosiglitazone is metabolised by CYP2C9 and CYP2C8. The biguanide metformin is not significantly metabolised but polymorphisms in the organic cation transporter (OCT) 1 and OCT2 may determine its pharmacokinetic variability. In conclusion, pharmacogenetic variability plays an important role in the pharmacokinetics of oral antidiabetic drugs; however, to date, the impact of this variability on clinical outcomes in patients is mostly unknown and prospective studies on the medical benefit of CYP genotyping are required.
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PMID:Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. 1637 21

Type 2 diabetes mellitus is a complex disease combining defects in insulin secretion and insulin action. New compounds called thiazolidinediones or glitazones have been developed for reducing insulin resistance. After the withdrawal of troglitazone because of liver toxicity, two compounds are currently used in clinical practice, rosiglitazone and pioglitazone. These compounds are generally used in combination with other pharmacological agents. Because they are metabolised via cytochrome P450 (CYP), glitazones are exposed to numerous pharmacokinetic interactions. CYP2C8 and CYP3A4 are the main isoenzymes catalysing biotransformation of pioglitazone (as with troglitazone), whereas rosiglitazone is metabolised by CYP2C9 and CYP2C8. For both rosiglitazone and pioglitazone, the most relevant interactions have been described in healthy volunteers with rifampicin (rifampin), which results in a significant decrease of area under the plasma concentration-time curve [AUC] (54-65% for rosiglitazone, p<0.001; 54% for pioglitazone, p<0.001), and with gemfibrozil, which results in a significant increase of AUC (130% for rosiglitazone, p<0.001; 220-240% for pioglitazone, p<0.001). The relevance of such drug-drug interactions in patients with type 2 diabetes remains to be evaluated. However, in the absence of clinical data, it is prudent to reduce the dosage of each glitazone by half in patients treated with gemfibrozil. Conversely, rosiglitazone and pioglitazone do not seem to significantly affect the pharmacokinetics of other compounds. Although some food components have also been shown to potentially interfere with drugs metabolised with the CYP system, no published study deals specifically with these possible CYP-mediated food-drug interactions with glitazones.
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PMID:Pharmacokinetic interactions with thiazolidinediones. 1720 56

Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC(0-infinity) geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t(1/2), or C(24 h), suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism.
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PMID:Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. 1724 67

This review describes the current knowledge on drug-drug and food-drug interactions with repaglinide and nateglinide. These two meglitinide derivatives, commonly called glinides, have been developed for improving insulin secretion of patients with type 2 diabetes mellitus. They are increasingly used either in monotherapy or in combination with other oral antihyperglycaemic agents for the treatment of type 2 diabetes. Compared with sulfonylureas, glinides have been shown to (i) provide a better control of postprandial hyperglycaemia, (ii) overcome some adverse effects, such as hypoglycaemia, and (iii) have a more favourable safety profile, especially in patients with renal failure. The meal-related timing of administration of glinides and the potential influence of food and meal composition on their bioavailability may be important. In addition, some food components (e.g. grapefruit juice) may cause pharmacokinetic interactions. Because glinides are metabolised via cytochrome P450 (CYP) 3A4 isoenzyme, they are indeed exposed to pharmacokinetic interactions. In addition to CYP3A4, repaglinide is metabolised via CYP2C8, while nateglinide metabolism also involves CYP2C9. Furthermore, both compounds and their metabolites may undergo specialised transport/uptake in the intestine, another source of pharmacokinetic interactions. Clinically relevant drug-drug interactions are those that occur when glinides are administered together with other glucose-lowering agents or compounds widely coadministered to diabetic patients (e.g. lipid-lowering agents), with drugs that are known to induce (risk of lower glinide plasma levels and thus of deterioration of glucose control) or inhibit (risk of higher glinide plasma levels leading to hypoglycaemia) CYP isoenzymes concerned in their metabolism, or with drugs that have a narrow efficacy : toxicity ratio. Pharmacokinetic interactions reported in the literature appear to be more frequent and more important with repaglinide than with nateglinide. Rifampicin (rifampin) reduced repaglinide area under the plasma concentration-time curve (AUC) by 32-85% while it reduced nateglinide AUC by almost 25%. Reported increases in AUCs with coadministration of drugs inhibiting CYP isoenzymes never exceeded 80% for repaglinide (except with ciclosporin and with gemfibrozil) and 50% for nateglinide. Ciclosporin more than doubled repaglinide AUC (+144%), a finding that should raise caution when using these two drugs in combination. The most impressive pharmacokinetic interaction was reported with combined administration of gemfibrozil (a strong CYP2C8 inhibitor) and repaglinide (8-fold increase in repaglinide AUC). Although no studies have been performed in patients with type 2 diabetes, the latter combination should be avoided in clinical practice.
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PMID:Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide. 1725 83

Although several environmental factors, including a high-calorie diet and physical inactivity, influence the development of type 2 diabetes mellitus, genetic factors have been shown to contribute to individual susceptibility to this condition. The purpose of the present study was to identify gene polymorphisms that confer susceptibility or resistance to type 2 diabetes mellitus, and thereby to contribute to assessment of the genetic risk for this condition. The study population comprised 5259 unrelated Japanese individuals (2980 men, 2279 women), including 1640 subjects with type 2 diabetes mellitus (1071 men, 569 women) and 3619 controls (1909 men, 1710 women). The genotypes for 94 polymorphisms of 67 genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Evaluation of genotype distributions by the chi-square test revealed that the 13989-->G (Ile118Val) polymorphism of the cytochrome P450, subfamily IIIA, polypeptide 4 gene (CYP3A4) was significantly (false discovery rate, 0.000009) associated with the prevalence of type 2 diabetes mellitus. Multivariable logistic regression analysis with adjustment for age and sex also revealed that the 13989-->G (Ile118Val) polymorphism of CYP3A4 was significantly (P=0.00002) associated with the prevalence of type 2 diabetes mellitus, with the AG genotype being protective against this condition. Genotyping for CYP3A4 may thus prove informative for assessment of the genetic risk for type 2 diabetes mellitus.
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PMID:Association of a polymorphism of CYP3A4 with type 2 diabetes mellitus. 1791 64

4-Chloro-N-(2-methyl-1-indolinyl)-3-sulfamoylbenzamide (indapamide), an indoline-containing diuretic drug, has recently been evaluated in a large Phase III clinical trial (ADVANCE) with a fixed-dose combination of an angiotensin-converting enzyme inhibitor, perindopril, and shown to significantly reduce the risks of major vascular toxicities in people with type 2 diabetes. The original metabolic studies of indapamide reported that the indoline functional group was aromatized to indole through a dehydrogenation pathway by cytochromes P450. However, the enzymatic efficiency of indapamide dehydrogenation was not elucidated. A consequence of indoline aromatization is that the product indoles might have dramatically different therapeutic potencies. Thus, studies that characterize dehydrogenation of the functional indoline of indapamide were needed. Here we identified several indapamide metabolic pathways in vitro with human liver microsomes and recombinant CYP3A4 that include the dehydrogenation of indapamide to its corresponding indole form, and also hydroxylation and epoxidation metabolites, as characterized by liquid chromatography/mass spectrometry. Indapamide dehydrogenation efficiency (V(max)/K(m)=204 min/mM) by CYP3A4 was approximately 10-fold greater than that of indoline dehydrogenation. In silico molecular docking of indapamide into two CYP3A4 crystal structures, to evaluate the active site parameters that control dehydrogenation, produced conflicting results about the interactions of Arg212 with indapamide in the active site. These conflicting theories were addressed by functional studies with a CYP3A4R212A mutant enzyme, which showed that Arg212 does not seem to facilitate positioning of indapamide for dehydrogenation. However, the metabolites of indapamide were precisely consistent with in silico predictions of binding orientations using three diverse computer methods to predict drug metabolism pathways.
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PMID:Dehydrogenation of the indoline-containing drug 4-chloro-N-(2-methyl-1-indolinyl)-3-sulfamoylbenzamide (indapamide) by CYP3A4: correlation with in silico predictions. 1907 30

Patients with type 2 diabetes mellitus (T2DM) are generally treated with many pharmacological compounds and are exposed to a high risk of drug-drug interactions. Indeed, blood glucose control usually requires a combination of various glucose-lowering agents, and the recommended global approach to reduce overall cardiovascular risk generally implies administration of several protective compounds, including HMG-CoA reductase inhibitors (statins), antihypertensive compounds and antiplatelet agents. New compounds have been developed to improve glucose-induced beta-cell secretion and glucose control, without inducing hypoglycaemia or weight gain, in patients with T2DM. Dipeptidylpeptidase-4 (DPP-4) inhibitors are novel oral glucose-lowering agents, which may be used as monotherapy or in combination with other antidiabetic compounds, metformin, thiazolidinediones or even sulfonylureas. Sitagliptin, vildagliptin and saxagliptin are already on the market, either as single agents or in fixed-dose combined formulations with metformin. Other compounds, such as alogliptin and linagliptin, are in a late phase of development. This review summarizes the available data on drug-drug interactions reported in the literature for these five DDP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin. Possible pharmacokinetic interferences have been investigated between each of these compounds and various pharmacological agents, which were selected because there are other glucose-lowering agents (metformin, glibenclamide [glyburide], pioglitazone/rosiglitazone) that may be prescribed in combination with DPP-4 inhibitors, other drugs that are currently used in patients with T2DM (statins, antihypertensive agents), compounds that are known to interfere with the cytochrome P450 (CYP) system (ketoconazole, diltiazem, rifampicin [rifampin]) or with P-glycoprotein transport (ciclosporin), or agents with a narrow therapeutic safety window (warfarin, digoxin). Generally speaking, almost no drug-drug interactions or only minor drug-drug interactions have been reported between DPP-4 inhibitors and any of these drugs. The gliptins do not significantly modify the pharmacokinetic profile and exposure of the other tested drugs, and the other drugs do not significantly alter the pharmacokinetic profile of the gliptins or exposure to these. The only exception concerns saxagliptin, which is metabolized to an active metabolite by CYP3A4/5. Therefore, exposure to saxagliptin and its primary metabolite may be significantly modified when saxagliptin is coadministered with specific strong inhibitors (ketoconazole, diltiazem) or inducers (rifampicin) of CYP3A4/5 isoforms. The absence of significant drug-drug interactions could be explained by the favourable pharmacokinetic characteristics of DPP-4 inhibitors, which are not inducers or inhibitors of CYP isoforms and are not bound to plasma proteins to a great extent. Therefore, according to these pharmacokinetic findings, which were generally obtained in healthy young male subjects, no dosage adjustment is recommended when gliptins are combined with other pharmacological agents in patients with T2DM, with the exception of a reduction in the daily dosage of saxagliptin when this drug is used in association with a strong inhibitor of CYP3A4/A5. It is worth noting, however, that a reduction in the dose of sulfonylureas is usually recommended when a DPP-4 inhibitor is added, because of a pharmacodynamic interaction (rather than a pharmacokinetic interaction) between the sulfonylurea and the DPP-4 inhibitor, which may result in a higher risk of hypoglycaemia. Otherwise, any gliptin may be combined with metformin or a thiazolidinedione (pioglitazone, rosiglitazone), leading to a significant improvement in glycaemic control without an increased risk of hypoglycaemia or any other adverse event in patients with T2DM. Finally, the absence of drug-drug interactions in clinical trials in healthy subjects requires further evidence from large-scale studies, including typical subjects with T2DM - in particular, multimorbid and geriatric patients receiving polypharmacy.
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PMID:Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions. 2069 Jul 81


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