Drug interactions of clinical importance with antihyperglycaemic agents: an update.

Because management of type 2 diabetes mellitus usually involves combined pharmacological therapy to obtain adequate glucose control and treatment of concurrent pathologies (especially dyslipidaemia and arterial hypertension), drug-drug interactions must be carefully considered with antihyperglycaemic drugs. Additive glucose-lowering effects have been extensively reported when combining sulphonylureas (or the new insulin secretagogues, meglitinide derivatives, i.e. nateglinide and repaglinide) with metformin, sulphonylureas (or meglitinide derivatives) with thiazolidinediones (also called glitazones) and the biguanide compound metformin with thiazolidinediones. Interest in combining alpha-glucosidase inhibitors with either sulphonylureas (or meglitinide derivatives), metformin or thiazolidinediones has also been demonstrated. These combinations result in lower glycosylated haemoglobin (HbA(1c)), fasting glucose and postprandial glucose levels than with either monotherapy. Even if modest pharmacokinetic interferences have been reported with some combinations, they do not appear to have important clinical consequences. No significant adverse effects, except a higher risk of hypoglycaemic episodes that may be attributed to better glycaemic control, occur with any combination. Challenging the classical dual therapy with sulphonylurea plus metformin, there is a recent trend to use alternative dual combinations (sulphonylurea plus thiazolidinedione or metformin plus thiazolidinedione). In addition, triple therapy with the addition of a thiazolidinedione to the metformin-sulphonylurea combination has been recently evaluated and allows glucose targets to be reached before insulin therapy is considered. This triple therapy appears to be safe, with no deleterious drug-drug interactions being reported so far.Potential interferences may also occur between glucose-lowering agents and other drugs, and such drug-drug interactions may have important clinical implications. Relevant pharmacological agents are those that are widely coadministered in diabetic patients (e.g. lipid-lowering agents, antihypertensive agents); those that have a narrow efficacy/toxicity ratio (e.g. digoxin, warfarin); or those that are known to induce (rifampicin [rifampin]) or inhibit (fluconazole) the cytochrome P450 (CYP) system. Metformin is currently a key compound in the pharmacological management of type 2 diabetes, used either alone or in combination with other antihyperglycaemics. There are no clinically relevant metabolic interactions with metformin, because this compound is not metabolised and does not inhibit the metabolism of other drugs. In contrast, sulphonylureas, meglitinide derivatives and thiazolidinediones are extensively metabolised in the liver via the CYP system and thus, may be subject to drug-drug metabolic interactions. Many HMG-CoA reductase inhibitors (statins) are also metabolised via the CYP system. Even if modest pharmacokinetic interactions may occur, it is not clear whether drug-drug interactions between oral antihyperglycaemic agents and statins may have clinical consequences regarding both efficacy and safety. In contrast, a marked pharmacokinetic interference has been reported between gemfibrozil and repaglinide and, to a lesser extent, between gemfibrozil and rosiglitazone. This leads to a drastic increase in plasma concentrations of each antihyperglycaemic agent when they are coadministered with the fibric acid derivative, and an increased risk of adverse effects.Some antihypertensive agents may favour hypoglycaemic episodes when co-prescribed with sulphonylureas or meglitinide derivatives, especially ACE inhibitors, but this effect seems to result from a pharmacodynamic drug-drug interaction rather than from a pharmacokinetic drug-drug interaction. No, or only modest, interferences have been described with glucose-lowering agents and other pharmacological compounds such as digoxin or warfarin. The effects of inducers or inhibitors of CYP isoenzymes on the metabolism and pharmacokinetics of the glucose-lowering agents of each pharmacological class has been tested. Significantly increased (with CYP inhibitors) or decreased (with CYP inducers) plasma levels of sulphonylureas, meglitinide derivatives and thiazolidinediones have been reported in healthy volunteers, and these pharmacokinetic changes may lead to enhanced or reduced glucose-lowering action, and thus hypoglycaemia or worsening of metabolic control, respectively. In addition, some case reports have evidenced potential drug-drug interactions with various antihyperglycaemic agents that are usually associated with a higher risk of hypoglycaemia.     

Pharmacokinetic interactions with thiazolidinediones

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.     

Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide

BACKGROUND AND AIMS: Gemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration-time curve [AUC(0, infinity)] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro, gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4. METHODS: In a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h. RESULTS: During the gemfibrozil-itraconazole phase, the AUC(0, infinity) and C(max) of nateglinide were 47% (range 23-74%; P < 0.0001) and 30% (range - 8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the t(max) and t1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole. CONCLUSIONS: The combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.     

格列奈类药物的药动学及与其他药物的相互作用

格列奈类药物吸收迅速,t_(1/2)短,单一疗法耐受性良好,不良反应发生率低于磺脲类药物,但与其他药物联用时,可能发生与CYP3A4、CYP2C8及CYP2C9同工酶和有机阴离子转运多肽1B1(OATP1B1)转运体相关的药动学相互作用,从而降低药物疗效或增加低血糖等不良事件的风险。本文就格列奈类药物的药动学性质及与其他药物的药动学相互作用作一综述。     

Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin

Repaglinide is an antidiabetic drug metabolised by cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes. To clarify the mechanisms of observed repaglinide drug interactions, we determined the contribution of the two enzymes to repaglinide metabolism at different substrate concentrations, and examined the effect of fibrates and rifampicin on CYP2C8, CYP3A4 and repaglinide metabolism in vitro. We studied repaglinide metabolism using pooled human liver microsomes, recombinant CYP2C8 and recombinant CYP3A4 enzymes. The effect of quercetin and itraconazole on repaglinide metabolism, and of gemfibrozil, bezafibrate, fenofibrate and rifampicin on CYP2C8 (paclitaxel 6alpha-hydroxylation) and CYP3A4 (midazolam 1-hydroxylation) activities and repaglinide metabolism were studied using human liver microsomes. At therapeutic repaglinide concentrations (<0.4 microM), CYP2C8 and CYP3A4 metabolised repaglinide at similar rates. Quercetin (25 microM) and itraconazole (3 microM) inhibited the metabolism of 0.2 microM repaglinide by 58% and 71%, and that of 2 microM repaglinide by 56% and 59%, respectively. The three fibrates inhibited CYP2C8 (Ki: bezafibrate 9.7 microM, gemfibrozil 30.4 microM and fenofibrate 92.6 microM) and repaglinide metabolism (IC50: bezafibrate 37.7 microM, gemfibrozil 111 microM and fenofibrate 164 microM), but had no effect on CYP3A4. Rifampicin inhibited CYP2C8 (Ki 30.2 microM), CYP3A4 (Ki 18.5 microM) and repaglinide metabolism (IC50 13.7 microM). In conclusion, both CYP2C8 and CYP3A4 are important in the metabolism of therapeutic concentrations of repaglinide in vitro, but their predicted contributions in vivo are highly dependent on the scaling factor used. Gemfibrozil is only a moderate inhibitor of CYP2C8 and does not inhibit CYP3A4; inhibition of CYP-enzymes by parent gemfibrozil alone does not explain its interaction with repaglinide in vivo. Rifampicin competitively inhibits both CYP2C8 and CYP3A4, which can counteract its inducing effect in humans.     

Mechanistic Modeling to Predict the Transporter- and Enzyme-Mediated Drug-Drug Interactions of Repaglinide

Purpose

Quantitative prediction of complex drug-drug interactions (DDIs) is challenging. Repaglinide is mainly metabolized by cytochrome-P-450 (CYP)2C8 and CYP3A4, and is also a substrate of organic anion transporting polypeptide (OATP)1B1. The purpose is to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics and DDIs of repaglinide.

Methods

In vitro hepatic transport of repaglinide, gemfibrozil and gemfibrozil 1-O-β-glucuronide was characterized using sandwich-culture human hepatocytes. A PBPK model, implemented in Simcyp (Sheffield, UK), was developed utilizing in vitro transport and metabolic clearance data.

Results

In vitro studies suggested significant active hepatic uptake of repaglinide. Mechanistic model adequately described repaglinide pharmacokinetics, and successfully predicted DDIs with several OATP1B1 and CYP3A4 inhibitors (<10% error). Furthermore, repaglinide-gemfibrozil interaction at therapeutic dose was closely predicted using in vitro fraction metabolism for CYP2C8 (0.71), when primarily considering reversible inhibition of OATP1B1 and mechanism-based inactivation of CYP2C8 by gemfibrozil and gemfibrozil 1-O-β-glucuronide.

Conclusions

This study demonstrated that hepatic uptake is rate-determining in the systemic clearance of repaglinide. The model quantitatively predicted several repaglinide DDIs, including the complex interactions with gemfibrozil. Both OATP1B1 and CYP2C8 inhibition contribute significantly to repaglinide-gemfibrozil interaction, and need to be considered for quantitative rationalization of DDIs with either drug.     

Prediction of the metabolic interaction of nateglinide with other drugs based on in vitro studies

Nateglinide is an antidiabetic agent metabolized by CYP2C9 and CYP3A4; hence inhibitors of these CYP isozymes may interact with nateglinide. There are, however, only limited in vitro data on how to predict drug-drug interactions in vivo. We examined the effects of 18 drugs that may be prescribed together with nateglinide (metformin, buformin, aspirin, gemfibrozil, simvastatin, pioglitazone, rosiglitazone, carbamazepine, clarithromycin, gliclazide, clofibrate, fluconazole, bezafibrate, phenylbutazone, nifedipine, famotidine, ibuprofen and miconazole) on the conversion of nateglinide to its major metabolite (N-[trans-4-(1-hydroxy-1-methylethyl)-cyclohexanecarbonyl]-D-phenylalanine) using human liver microsomes. Eight compounds showed a<50% inhibitory effect and we estimated the K(i) values for the remaining 10 compounds. Except for fluconazole and miconazole, 1+I(in, max, u)/K(i) calculated from the K(i) values, was approximately 1 and thus the possibility of a drug-drug interaction was considered low. The value for fluconazole suggested the risk of interaction and agreed with the results of clinical studies in which the AUC of nateglinide increased by 48% when it was co-administered with fluconazole. The present study showed that nateglinide metabolism would hardly be affected by the drugs used in this study, except for miconazole and fluconazole that are potent inhibitors of multiple isoforms of CYPs.     

Clinical pharmacokinetics of nateglinide: a rapidly-absorbed, short-acting insulinotropic agent

The prevalence and medical and economic impact of type 2 diabetes mellitus is increasing in Western societies. New agents have been developed that act primarily to reduce postprandial glucose excursions, which may be of particular significance now that postprandial glucose excursions are known to be correlated with cardiovascular morbidity and mortality. Nateglinide is a phenylalanine derivative that blocks K+ channels in pancreatic beta-cells, facilitating insulin secretion. Nateglinide sensitises beta-cells to ambient glucose, reducing the glucose concentration needed to stimulate insulin secretion. The pharmacokinetics of nateglinide are characterised by rapid absorption and elimination, with good (73%) bioavailability. Nateglinide is more rapidly absorbed when given 0-30 minutes prior to meal ingestion than if given during the meal. Nateglinide is extensively metabolised, primarily by cytochrome P450 2C9, and eliminated primarily by the kidney. Nateglinide pharmacokinetics are linear over the dose range 60-240 mg. No significant pharmacokinetic alterations occur in renally impaired patients, in the elderly, or in mildly hepatically impaired patients. Nateglinide administered prior to meals stimulates rapid, short-lived insulin secretion in a dose-dependent manner, thus decreasing mealtime plasma glucose excursions. Its effects on insulin secretion are synergistic with those of a meal. With increasing nateglinide doses, the risk of hypoglycaemia also increases, but its incidence is low. Even if a meal is missed, and the patient skips the dose of nateglinide (as recommended in the event of a missed meal), the incidence of subsequent hypoglycaemia remains low compared with long-acting agents. The postprandial insulinotropic effects of nateglinide are more rapid than those of repaglinide and more rapid and greater than those of glibenclamide (glyburide), while producing less prolonged insulin exposure and less risk of delayed hypoglycaemia. Further investigation is required to determine if nateglinide inhibition of postprandial glucose excursions will help to prevent diabetic complications or preserve pancreatic beta-cell function.     

Meglitinide analogues in the treatment of type 2 diabetes mellitus

Type 2 diabetes mellitus is a complex heterogenous metabolic disorder in which peripheral insulin resistance and impaired insulin release are the main pathogenetic factors. The rapid response of the pancreatic beta-cells to glucose is already markedly disturbed in the early stages of type 2 diabetes mellitus. The consequence is often postprandial hyperglycaemia, which seems to be extremely important in the development of secondary complications, especially macrovascular disease. Therefore one of the main aims of treatment is to minimise blood glucose oscillations and attain near-normal glycosylated haemoglobin levels. Meglitinide analogues belong to a new family of insulin secretagogues which stimulate insulin release by inhibiting ATP-sensitive potassium channels of the beta-cell membrane via binding to a receptor distinct from that of sulphonylureas (SUR1/KIR 6.2). The pharmacokinetic and pharmacodynamic properties of repaglinide, the first drug of these new antihyperglycaemic agents on the market, and of nateglinide, which will be available soon, differ markedly from the currently used sulphonylureas [mainly glibenclamide (glyburide) and glimepiride]. Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, are rapidly metabolised in the liver and are mainly excreted in the bile. Therefore, following preprandial administration of these drugs, insulin is more readily available during and just after the meal. This leads to a significant reduction in postprandial hyperglycaemia without the danger of hypoglycaemia between meals. The short action of these compounds and biliary elimination makes repaglinide and nateglinide especially suitable for patients with type 2 diabetes mellitus who would like to have a more flexible lifestyle, need more flexibility because of unplanned eating behaviour (e.g. geriatric patients) or in whom one of the other first-line antidiabetic drugs, i.e. metformin, is strictly contraindicated (e.g. nephropathy with creatinine clearance < or = 50 ml/min). Meglitinide analogues act synergistically with metformin and thiazolidinediones (pioglitazone and rosiglitazone) and can be also combined with long-acting insulin (NPH insulin at bedtime). Therefore, these drugs enrich the palette of antidiabetic drugs and make the treatment more flexible and better tolerated, which both add to better metabolic control and support the empowerment and compliance of the patient. However, this will only be the case if the patient and the diabetes care team are trained for this new therapeutic schedule and the healthcare system is able to pay for these rather expensive drugs.     

A review of clinical experience with the prandial glucose regulator,repaglinide, in the treatment of Type 2 diabetes

Repaglinide is a novel insulin secretagogue that was developed as a prandial glucose regulator for the treatment of people with Type 2 diabetes mellitus. It is used flexibly, taken prior to meals, in order to limit subsequent postprandial blood glucose excursions as well as the dependent basal blood glucose concentration. In theory, the pharmacological profile of repaglinide is well suited for this role. Taken at mealtimes, its relatively rapid-onset and short-duration of action counteract a fundamental pathophysiological aspect of this disease: attenuation of the prandial insulin response. The predominantly hepatic elimination profile and a lack of drug-drug interactions with repaglinide are also properties well suited for patients with Type 2 diabetes. Importantly, the pharmacokinetic properties of repaglinide, are expected to reduce the risk of hypoglycaemia in comparison to the conventional insulin secretagogues (sulphonylureas). A reduced risk of hypoglycaemia carries the advantage that patients are not obliged to consume meals at regular intervals supplemented by snacks, so caloric restriction is feasible and lifestyle not compromised.     

Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance

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.     

Investigation of sarizotan’s impact on the pharmacokinetics of probe drugs for major cytochrome P450 isoenzymes: a combined cocktail trial

Objective The 5HT_1A receptor agonist sarizotan is in clinical development for the treatment of dyskinesia, a potentially disabling complication in Parkinson’s disease. We investigated the effect of sarizotan on the clinical pharmacokinetics of probe drugs for cytochrome P450 (CYP) to evaluate the risk of CYP-related drug-drug interactions. Methods This was a double-blind, randomised, two-period cross-over interaction study with repeated administration of 5 mg sarizotan HCl or placebo b.i.d. for 8 days in 18 healthy volunteers. On day 4, a single dose of 100 mg metoprolol (CYP2D6 probe) was administered. On day 8, single doses of 100 mg caffeine (CYP1A2 probe), 50 mg diclofenac (CYP2C9 probe), 100 mg mephenytoin (CYP2C19 probe) and 7.5 mg midazolam (CYP3A4 probe) were simultaneously applied. Pharmacokinetic parameters for probe drugs and their metabolites in plasma and urinary recovery were determined. Results Concentration-time profiles and pharmacokinetic parameters of all probes and their metabolites remained unchanged after co-administration of sarizotan, compared with placebo. Analysis of variance of the area under the plasma concentration-time curve for probe drugs/metabolites, metabolic ratios and urinary excretion resulted in 90% confidence intervals within the acceptance range (0.8–1.25), indicating the absence of drug-drug interactions. Conclusions At a dose higher than that intended for clinical use (1 mg b.i.d.), sarizotan had no effect on the metabolism and pharmacokinetics of specific probe drugs for CYP isoenzymes 1A2, 2C19, 2C9, 2D6 and 3A4. Pharmacokinetic interactions with co-administered drugs metabolised by these CYP isoforms are not expected, and dose adjustment of co-administered CYP substrates is not necessary.     

Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach

Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes.     

Drug interaction potential of toremifene and N-desmethyltoremifene with multiple cytochrome P450 isoforms

Toremifene is an effective agent for the treatment of breast cancer in postmenopausal women and is being evaluated for its ability to prevent bone fractures in men with prostate cancer taking androgen deprivation therapy. Due to the potential for drug-drug interactions, the ability of toremifene and its primary circulating metabolite N-desmethyltoremifene (NDMT) to inhibit nine human cytochrome P450 (CYP) enzymes was determined using human liver microsomes. Induction of CYP1A2 and 3A4 by toremifene was also investigated in human hepatocytes. Toremifene did not significantly inhibit CYP1A2 or 2D6. However, toremifene is a competitive inhibitor of CYP3A4, non-competitive inhibitor of CYP2A6, 2C8, 2C9, 2C19 and 2E1 and mixed-type inhibitor of CYP2B6. CYP inhibition by NDMT was similar in magnitude to toremifene. Toremifene did not induce CYP1A2 but increased CYP3A4 monooxygenase activity and gene expression in drug-exposed human primary hepatocytes. Although clinical doses of toremifene produce steady state exposures to toremifene and NDMT that may be sufficient to cause pharmacokinetic drug-drug interactions with other drugs metabolised by CYP2B6, CYP2C8, CYP3A4, CYP2C9 and CYP2C19, these data indicate that toremifene is unlikely to play a role in clinical drug-drug interactions with substrate drugs of CYP1A2 and CYP2D6.     

CYP3A4 and MDR Mediated Interactions in Drug Therapy

Multiple drug therapy is recommended in many disease states including AIDS, cancer, diabetes, and stroke. Therefore, drug-drug interactions can result in changes in pharmacological or toxicological response following concomitant administration of many therapeutic agents. It has become evident that two factors i.e. drug efflux pump- P-glycoprotein (MDR gene product) and metabolizing enzyme- CYP3A4 play major roles in this process. These two key proteins regulate all pharmacokinetic and pharmacodynamic interactions through the process of drug absorption, metabolism, disposition and elimination. Co-administration of two or more drugs can affect these processes due to altered functions of P-glycoprotein (P-gp) and CYP3A4 and consequently change clinical response and final outcome. After co-administration, some drugs may induce the activity of P-gp and/or CYP3A4 resulting in subtherapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. Conversely, inhibition(s) of P-gp and/or CYP3A4 can cause enhanced plasma concentration and therefore, drug toxicity. Overlapping substrate specificities to these proteins make it difficult to understand perplexing pharmacokinetic interactions with multidrug regimens. Inter-patient variability of drug response can occur due to change in genetic profiles, intake of food, herbal supplement, and recreational drugs. In this review, we have outlined several clinically important CYP and MDR-mediated drug-drug interactions of antiretroviral agents, antineoplastic agents, azole antifungals, statins, methadone, antibacterials, cardiovascular medicines, immune modulators, recreational drugs and herbal agents. Mechanisms by which such drug interactions occur have been briefly discussed in some of the examples.     

Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus

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 (相似文献   

Influence of drugs interacting with CYP3A4 on the pharmacokinetics,pharmacodynamics, and safety of the prandial glucose regulator repaglinide

The object of this study was to analyze drug interactions between repaglinide, a short-acting insulin secretagogue, and five other drugs interacting with CYP3A4: ketoconazole, rifampicin, ethinyloestradiol/levonorgestrel (in an oral contraceptive), simvastatin, and nifedipine. In two open-label, two-period, randomized crossover studies, healthy subjects received repaglinide alone, repaglinide on day 5 of ketoconazole treatment, or repaglinide on day 7 of rifampicin treatment. In three open-label, three-period, randomized crossover studies, healthy subjects received 5 days of repaglinide alone; 5 days of ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine alone; or 5 days of repaglinide concomitant with ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. Compared to administration of repaglinide alone, concomitant ketoconazole increased mean AUC0-infinity for repaglinide by 15% and mean Cmax by 7%. Concomitant rifampicin decreased mean AUC0-infinity for repaglinide by 31% and mean Cmax by 26%. Concomitant treatment with CYP3A4 substrates altered mean AUC0-5 h and mean Cmax for repaglinide by 1% and 17% (ethinyloestradiol/levonorgestrel), 2% and 27% (simvastatin), or 11% and 3% (nifedipine). Profiles of blood glucose concentration following repaglinide dosing were altered by less than 8% by both ketoconazole and rifampicin. In all five studies, most adverse events were related to hypoglycemia, as expected in a normal population given a blood glucose regulator. The safety profile of repaglinide was not altered by pretreatment with ketoconazole or rifampicin or by coadministration with ethinyloestradiol/levonorgestrel. The incidence of adverse events increased with coadministration of simvastatin or nifedipine compared to either repaglinide or simvastatin/nifedipine treatment alone. No clinically relevant pharmacokinetic interactions occurred between repaglinide and the CYP3A4 substrates ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. The pharmacokinetic profile of repaglinide was altered by administration of potent inhibitors or inducers, such as ketoconazole or rifampicin, but to a lesser degree than expected. These results are probably explained by the metabolic pathway of repaglinide that involves other enzymes than CYP3A4, reflected to some extent by a small change in repaglinide pharmacodynamics. Thus, careful monitoring of blood glucose in repaglinide-treated patients receiving strong inhibitors or inducers of CYP3A4 is recommended, and an increase in repaglinide dose may be necessary. No safety concerns were observed, except a higher incidence in adverse events in patients receiving repaglinide and simvastatin or nifedipine.     

那格列奈和瑞格列奈治疗2型糖尿病效果和安全性的Meta分析

目的:评价那格列奈和瑞格列奈治疗2型糖尿病的有效性和安全性。方法:应用Meta分析对6篇研究那格列奈和瑞格列奈治疗糖尿病有效性、安全性的文献进行同质性检验及合并效应量估计。结果:6篇随机对照试验,共纳入811名患者。Meta分析结果显示,那格列奈和瑞格列奈比较,疗效和安全性无统计性意义。结论:那格列奈和瑞格列奈治疗2型糖尿病的疗效和安全性无差异,还需进行更多、更严格的多中心随机双盲对照试验。