Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite,norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin

This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5–64.8%, and the peak plasma concentration (C_max) of verapamil by 34.1–65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (T_max) and the terminal half-life (t_1/2) of verapamil in the presence of lovastatin. The AUC and C_max of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.     

The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits

We have investigated the effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. Pharmacokinetic parameters of verapamil and norverapamil were determined after the oral administration of verapamil (10 mg kg(-1)) to rabbits in the presence and absence of quercetin (5.0 and 15 mg kg(-1)). While co-administration of quercetin concurrently was not effective to enhance the oral exposure of verapamil, pretreatment of quercetin 30 min before verapamil administration significantly altered the pharmacokinetics of verapamil. Compared with the control group (given verapamil alone), the C(max) and AUC of verapamil increased approximately twofold in the rabbits pretreated with 15 mg kg(-1) quercetin. There was no significant change in T(max) and terminal plasma half-life (t(1/2)) of verapamil in the presence of quercetin. Consequently, absolute and relative bioavailability values of verapamil in the rabbits pretreated with quercetin were significantly higher (P < 0.05) than those from the control group. Metabolite-parent AUC ratio in the rabbits pretreated with quercetin decreased by twofold compared with the control group, implying that pretreatment of quercetin could be effective to inhibit the CYP3A4-mediated metabolism of verapamil. In conclusion, pretreatment of quercetin significantly enhanced the oral exposure of verapamil. This suggested that concomitant use of quercetin or a quercetin-containing dietary supplement with verapamil requires close monitoring for potential drug interaction.     

Effects of lovastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats: possible role of cytochrome P450 3A4 and P-glycoprotein inhibition by lovastatin

Objectives The purpose of this study was to examine the effects of lovastatin on cytochrome P450 (CYP) 3A4 and P‐glycoprotein (P‐gp) in vitro and then to determine the effects of lovastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats. Methods The pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after orally administering diltiazem (12 mg/kg) to rats in the presence and absence of lovastatin (0.3 and 1.0 mg/kg). The effect of lovastatin on P‐gp as well as CYP3A4 activity was also evaluated. Key findings Lovastatin inhibited CYP3A4 enzyme activity with a 50% inhibition concentration of 6.06 µM. In addition, lovastatin significantly enhanced the cellular accumulation of rhodamine‐123 in MCF‐7/ADR cells overexpressing P‐gp. Compared with the control (given diltiazem alone), the presence of lovastatin significantly altered the pharmacokinetic parameters of diltiazem. The areas under the plasma concentration–time curve (AUC) and the peak concentration of diltiazem were significantly increased (P < 0.05, 1.0 mg/kg) in the presence of lovastatin. Consequently, the absolute bioavailability values of diltiazem in the presence of lovastatin (11.1% at 1.0 mg/kg) were significantly higher (P < 0.05) than that of the control group (7.6%). The metabolite–parent AUC ratio in the presence of lovastatin (1.0 mg/kg) was significantly (P < 0.05) decreased compared with the control group. Conclusions It might be considered that lovastatin resulted in reducing the first‐pass metabolism in the intestine and/or in the liver via inhibition of CYP3A4 and increasing the absorption of diltiazem in the intestine via inhibition of P‐gp by lovastatin.     

Effects of simvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, after oral and intravenous administration in rats: possible role of P-glycoprotein and CYP3A4 inhibition by simvastatin

The purpose of this study was to investigate the possible effects of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats. HMG-CoA reductase inhibitors and diltiazem are sometimes prescribed as a combination therapy for the prevention or treatment of cardiovascular diseases. The effect of simvastatin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Simvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC(50)) of 3.0 μM. In addition, simvastatin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after oral and intravenous administration of diltiazem to rats in the presence and absence of simvastatin (0.3 and 1.0 mg/kg). The areas under the plasma concentration-time curve (AUC) and the peak concentration (C(max)) of diltiazem were significantly (p < 0.05, 1.0 mg/kg) increased by 45.2% and 35.2%, respectively, in the presence of simvastatin compared to control. Consequently, the absolute bioavailability (AB) values of diltiazem in the presence of simvastatin (1.0 mg/kg) were significantly (p < 0.05) higher (44.8%) than that of the control group. Moreover, the relative bioavailability (RB) of diltiazem was 1.21- to 1.45-fold greater than that in the control group. The metabolite-parent AUC ratio (MR) in the presence of simvastatin (1.0 mg/kg) significantly decreased compared to the control group. This result implied that simvastatin effectively inhibited the metabolism of diltiazem. The increase in diltiazem oral bioavailability might be attributable to enhanced absorption in the small intestine via the inhibition of P-gp and to reduced first-pass metabolism of diltiazem via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver rather than renal elimination of diltiazem by simvastatin.     

Effects of naringin on the pharmacokinetics of verapamil and one of its metabolites, norverapamil, in rabbits

It was reported that verapamil is metabolized via hepatic microsomal cytochrome P450 (CYP) 3A4 and that naringin (a component of grapefruit juice) inhibits CYP3A4 in humans. Hence, after oral administration of verapamil, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of verapamil and the AUC(verapamil)/AUC(D-617 (a metabolite of verapamil)) ratio were significantly greater after oral grapefruit juice in humans. The aim of this study was to determine whether similar results could be obtained from rabbits. The pharmacokinetics of verapamil and one of its metabolites, norverapamil, were investigated after oral administration of verapamil at a dose of 9 mg/kg without or with oral naringin at a dose of 7.5 mg/kg in rabbits. With naringin, the AUC of verapamil was significantly greater (28.4 versus 18.4 microg min/ml). Although, the AUC values of norverapamil were not significantly different between groups without and with naringin, the AUC(verapamil)/AUC(norverapamil) ratio was considerably greater (1.49 versus 1.11) with naringin. The above data suggested that the metabolism of verapamil and the formation of norverapamil was inhibited by naringin possibly by inhibition of CYP3A in rabbits.     

Effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats

The present study aimed to investigate the effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats. The pharmacokinetic parameters of verapamil were measured after an oral (9 mg/kg) or intravenous (3 mg/kg) administration of verapamil to rats in the presence and absence of atorvastatin. Compared with the control given verapamil alone, the concurrent use of 1.5 mg/kg of atorvastatin significantly increased the oral exposure of verapamil in rats. The AUC and C(max) of verapamil increased by 70% and 61%, respectively in the presence of atorvastatin (1.5 mg/kg), while there was no significant change in T(max) and the terminal plasma half-life (T(1/2)) of verapamil. Accordingly, the presence of atorvastatin significantly (p<0.05) increased the bioavailability of verapamil in rats. In contrast, atorvastatin had no effect on any pharmacokinetic parameters of verapamil given intravenously, implying that atorvastatin may improve the oral bioavailability of verapamil by reducing the prehepatic extraction of verapamil most likely mediated by P-gp and/or CYP3A4. In conclusion, coadministration of atorvastatin significantly enhanced the oral exposure of verapamil in rats without a change in the systemic clearance of intravenous verapamil, suggesting a potential drug interaction between verapamil and atorvastatin via the modulation of prehepatic extraction.     

Enhanced bioavailability of verapamil after oral administration with hesperidin in rats

The aim of this study was to investigate the effects of hesperidin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of hesperidin (3 or 10 mg/kg). Compared to the control group, the presence of hesperidin significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 71.1–96.8% and the peak concentration (C_max) of verapamil by 98.3–105.2%. Hesperidin significantly (p<0.01) decreased the total plasma clearance (CL/F) of verapamil by 41.6–49.2% in rats. However there was no significant change in the time to reach the peak plasma concentration (T_max), the elimination rate constant (K_el) and the terminal half-life (T_1/2) of verapamil in the presence of hesperidin. The AUC and C_max of norverapamil were significantly (p<0.05) higher in rats coadministrated with hesperidin than those of the control. Consequently hesperidin significantly enhanced bioavailability of verapamil in rats. These results might be due to the decreased efflux and metabolism of verapamil in the intestine. Drug interactions should be concerned in the clinical setting when verapamil is used concomitantly with hesperidin or hesperidin-containing dietary.     

Reduced prehepatic extraction of nicardipine in the presence of pioglitazone in rats

This study investigated the effect of pioglitazone on the pharmacokinetics of oral and i.v. nicardipine in rats. Pharmacokinetic parameters were determined after nicardipine was administered orally (12 mg kg(-1)) or i.v. (4 mg kg(-1)) with or without a single dose of oral pioglitazone (0.3 or 1.0 mg kg(-1)). Compared with the control group given nicardipine alone, coadministration of pioglitazone significantly decreased the total plasma clearance of orally administered nicardipine (by 40.4-46.3%, P < 0.05) and significantly increased the area under the plasma concentration-time curve (by 81.8-96.3%) and the peak plasma concentration, C(max) (by 56.5-66.8%). T(max) and the terminal plasma half-life of nicardipine were not affected, however. Coadministration of oral pioglitazone did not affect the pharmacokinetics of i.v. nicardipine, implying that pioglitazone may mainly decrease the prehepatic extraction of nicardipine during intestinal absorption. In conclusion, pioglitazone significantly enhanced the oral bioavailability of nicardipine in rats by reducing its presystemic clearance.     

Effects of the antioxidant baicalein on the pharmacokinetics of nimodipine in rats: a possible role of P-glycoprotein and CYP3A4 inhibition by baicalein

The reduced bioavailability of nimodipine after oral administration might not only be due to the metabolizing enzyme cytochrome P450 3A4(CYP3A4) but also to the P-glycoprotein efflux transporter in the small intestine. The aim of this study was to investigate the effects of baicalein on the pharmacokinetics of nimodipine in rats. The effect of baicalein on P-glycoprotein and CYP3A4 activity was evaluated. A single dose of nimodipine was administered intravenously (3 mg/kg) and orally (12 mg/kg) to rats in the presence and absence of baicalein (0.4, 2 and 8 mg/kg). Baicalein inhibited CYP3A4 enzyme activity in a concentration-dependent manner, with a 50% inhibition concentration (IC(50)) of 9.2 μM. In addition, baicalein significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-glycoprotein. Baicalein significantly altered the pharmacokinetics of orally administered nimodipine. Compared to the oral control group given nimodipine alone, the area under the plasma concentration-time curve (AUC(0-∞)) and the peak plasma concentration (C(max)) of nimodipine significantly increased (p < 0.05 for 2 mg/kg; p < 0.01 for 8 mg/kg). Consequently, the absolute bioavailability of nimodipine in the presence of baicalein (2 and 8 mg/kg) was 31.0-35.3%, which was significantly enhanced (p < 0.05 for 2 mg/kg; p < 0.01 for 8 mg/kg) compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.39- to 1.58-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine were not affected by baicalein in contrast to those of oral nimodipine. Baicalein significantly enhanced the oral bioavailability of nimodipine, which may be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and/or in the liver and the inhibition of the P-glycoprotein efflux pump in the small intestine by baicalein. The increase in oral bioavailability of nimodipine in the presence of baicalein should be taken into consideration as a potential drug interaction between nimodipine and baicalein.     

effect of atorvastatin on the pharmacokinetics of diltiazem and its main metabolite,desacetyldiltiazem, in rats

The purpose of this study was to investigate the effect of atorvastatin, HMG-CoA reductase inhibitor, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 mg x kg(-1)) to rats pretreated with atorvastatin (0.5 or 2.0 mg x kg(-1)). Compared with the control (given diltiazem alone), the pretreatment of atorvastatin significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration (Cmax) and the areas under the plasma concentration-time curve (AUC) of diltiazem were significantly (p < 0.05, 0.5 mg x kg(-1); p < 0.01, 2.0 mg x kg(-1)) increased in the presence of atorvastatin. The AUC of diltiazem was increased by 1.40-fold in rats pretreated with 0.5 mg x kg(-1) atorvastatin, and 1.77-fold in rats pretreated with 2.0 mg x kg(-1) atorvastatin. Consequently, absolute bioavailability values of diltiazem pretreated with atorvastatin (8.4-10.6%)were significantly higher (p < 0.05) than that in the control group (6.6%). Although the pretreatment of atorvastatin significantly (p < 0.05) increased the AUC of desacetyldiltiazem, metabolite-parent AUC ratio (M.R.) in the presence of atorvastatin (0.5 or 2.0 mg x kg(-1)) was significantly decreased compared to the control group, implying that atorvastatin could be effective to inhibit the metabolism of diltiazem. In conclusion, the concomitant use of atorvastatin significantly enhanced the oral exposure of diltiazem in rats.     

Pharmacokinetics of verapamil and its major metabolite, nor-verapamil from oral administration of verapamil in rabbits with hepatic failure induced by carbon tetrachloride

The aim of this study was to investigate the pharmacokinetic changes of verapamil and its major metabolite, norverapamil, after oral administration of verapamil (10 mg/kg) in rabbits with slight, moderate and severe hepatic failure induced by carbon tetrachloride. The plasma verapamil concentrations in all groups of hepatic failure were significantly higher (p < 0.01) than the control. However, the plasma norverapamil concentrations in severe hepatic failure were significantly higher (p < 0.05) than the control. The peak concentrations (Cmax) and the areas under the plasma concentration-time curve (AUC) of verapamil in the rabbits were significantly (p<0.01) higher than the control. The absolute bioavailability (F(A.B)) and the relative bioavailability (F(R.B)) of verapamil in the rabbits with hepatic failure were significantly higher (13.6-22.2% and 150-244%, respectively) than the control (9.1% and 100%, respectively). Although the AUC and Cmax of its major metabolite, norverapamil, in slight, moderate hepatic failure were not significantly lower than the control, the metabolite-parent AUC ratio in all groups of hepatic failure was decreased significantly (p < 0.05, in slight group; p < 0.01, in moderate and severe group) than the control. This could be due to decrease in metabolism of verapamil in the liver because of suppressed hepatic function in the hepatic failure groups because verapamil is mainly metabolized in the liver. From our data, it would seem appropriate that in patients with liver disease, doses of verapamil should be decreased by degree of hepatic failure.     

Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide

Objective Pioglitazone, a thiazolidinedione antidiabetic, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. Repaglinide, a meglitinide analogue antidiabetic, is metabolised by CYP2C8 and CYP3A4. In patients with type 2 diabetes, the pioglitazone-repaglinide combination has acted synergistically on glycaemic parameters. Our aim was to determine whether pioglitazone increases the plasma concentrations of repaglinide. Methods In a randomized, 2-phase cross-over study, 12 healthy volunteers received 30 mg pioglitazone or placebo once daily for 5 days. On day 5, they ingested a single 0.25 mg dose of repaglinide 1 h after the last pretreatment dose. Plasma repaglinide and pioglitazone, and blood glucose concentrations were measured for 12 h. Results During the pioglitazone phase, the mean peak plasma repaglinide concentration (C_max) and the total area under the concentration-time curve [AUC(0-∞)] of repaglinide were 100% (range 53–157%, P=0.99) and 90% (range 63–120%, P=0.22), respectively, of those during the placebo phase. Also the half-life of repaglinide was unaffected, but the median peak time of repaglinide was shortened from 40 min to 20 min by pioglitazone (P=0.014). The short-term pioglitazone administration did not modify the blood glucose-lowering effect of a single dose of repaglinide. Conclusions Pioglitazone does not increase the plasma concentrations of repaglinide, indicating that the inhibitory effect of pioglitazone on CYP2C8 and CYP3A4 is very weak in vivo, probably due to its extensive plasma protein binding. The synergistic effect of repaglinide and pioglitazone on the glycaemic parameters, seen in patients with type 2 diabetes during their long-term use, is unlikely to be caused by inhibition of repaglinide metabolism by pioglitazone.     

Quercetin pretreatment increases the bioavailability of pioglitazone in rats: involvement of CYP3A inhibition

Herbal antidiabetic preparations are often used as an add-on therapy in diabetes and such herbal preparations often contains quercetin that can inhibit cytochrome P450 (CYP) 3A4. This enzyme is responsible for metabolizing pioglitazone, a commonly used antidiabetic agent. Hence, it was speculated that quercetin may influence the bioavailability of pioglitazone, which could be particularly crucial, as any increment in its plasma levels may raise safety concerns. Thus, we first established the inhibitory influence of quercetin (2, 10 and 20 mg/kg, p.o.) on CYP3A activity by an in vivo method of estimating levels of midazolam in female rats pretreated with dexamethasone. It was further confirmed in vitro using erythromycin-N-demethylase (EMD) assay. These studies indicated potent inhibition of CYP3A activity by quercetin (10 and 20 mg/kg, in vivo; 1 and 10 microM, in vitro). In another experiment, pioglitazone was administered orally (10 mg/kg) and intravenously (5mg/kg) to quercetin (10 mg/kg) pretreated female rats and its plasma levels were determined at various time points (0.5, 1, 2, 4, 8 and 24 h after oral administration; 0.083, 0.5, 1, 2, 8, 12 and 18 h after i.v. administration) by HPLC. Quercetin pretreatment increased AUC(0-infinity) of pioglitazone after oral administration by 75% and AUC(0-infinity) after intravenous administration by 25% suggesting decreased metabolism, which could be due to inhibition of CYP3A by quercetin. In conclusion, add-on preparations containing quercetin may increase the bioavailability of pioglitazone, and hence should be cautiously used.     

Effect of pioglitazone on endotoxin-induced decreases in hepatic drug-metabolizing enzyme activity and expression of CYP3A2 and CYP2C11

It has been reported that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands ameliorate the expression of inducible nitric oxide synthase (iNOS) by endotoxin. In the present study, we investigated the effect of pioglitazone, a potent PPAR-gamma ligand, on the endotoxin-induced reduction of hepatic drug-metabolizing enzyme activity and on the down-regulation of the expression of hepatic cytochrome P450 (CYP) 3A2 and CYP2C11 proteins in rats. Endotoxin (1 mg/kg) significantly decreased hepatic drug-metabolizing enzyme activity in vivo, as represented by the systemic clearance of antipyrine and protein levels of CYP3A2 and CYP2C11 24 h after intraperitoneal injection. Pretreatment with pioglitazone (10 mg/kg, 4 times at 10-min intervals) significantly protected the endotoxin-induced decreases in the systemic clearance of antipyrine and protein levels of CYP3A2, but not CYP2C11, with no biochemical and histopathological changes in the liver. Pioglitazone alone had no effect on the systemic clearance of antipyrine and protein levels of CYP3A2 or CYP2C11. Pioglitazone significantly protected endotoxin-induced overexpression of iNOS in the liver, but not the overproduction of nitric oxide (NO) in plasma. It is unlikely that the protective effect of pioglitazone against endotoxin-induced decreases in the hepatic drug-metabolizing enzyme activity and protein levels of CYP3A2 in the liver is due to the inhibition of the overproduction of NO.     

Effect of rifampicin on the pharmacokinetics of pioglitazone

AIMS: The effect of enzyme induction on the pharmacokinetics of pioglitazone, a thiazolidinedione antidiabetic drug that is metabolized primarily by CYP2C8, is not known. Rifampicin is a potent inducer of several CYP enzymes and our objective was to study its effects on the pharmacokinetics of pioglitazone in humans. METHODS: In a randomized, two-phase crossover study, ten healthy subjects ingested either 600 mg rifampicin or placebo once daily for 6 days. On the last day, they received a single oral dose of 30 mg pioglitazone. The plasma concentrations and cumulative excretion of pioglitazone and its active metabolites M-IV and M-III into urine were measured up to 48 h. RESULTS: Rifampicin decreased the mean total area under the plasma concentration-time curve (AUC(0-infinity)) of pioglitazone by 54% (range 20-66%; P = 0.0007; 95% confidence interval -78 to -30%) and shortened its dominant elimination half-life (t(1/2)) from 4.9 to 2.3 h (P = 0.0002). No significant effect on peak concentration (C(max)) or time to peak (t(max)) was observed. Rifampicin increased the apparent formation rate of M-IV and shortened its t(max) (P < 0.01). It also decreased the AUC(0-infinity) of M-IV (by 34%; P = 0.0055) and M-III (by 39%; P = 0.0026), shortened their t1/2 (M-IV by 50%; P = 0.0008, and M-III by 55%; P = 0.0016) and increased the AUC(0-infinity) ratios of M-IV and M-III to pioglitazone by 44% (P = 0.0011) and 32% (P = 0.0027), respectively. Rifampicin increased the M-IV/pioglitazone and M-III/pioglitazone ratios in urine by 98% (P = 0.0015) and 95% (P = 0.0024). A previously unrecognized metabolite M-XI, tentatively identified as a dihydroxy metabolite, was detected in urine during both phases, and rifampicin increased the ratio of M-XI to pioglitazone by 240% (P = 0.0020). CONCLUSIONS: Rifampicin caused a substantial decrease in the plasma concentration of pioglitazone, probably by induction of CYP2C8. Concomitant use of rifampicin with pioglitazone may decrease the efficacy of the latter drug.     

Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: a 42-month, open-label, observational, primary care study

BACKGROUND: Insulin resistance and declining beta-cell function are the core defects in type 2 diabetes mellitus. It has been suggested that deteriorating glycemic control is related to baseline hemoglobin A(1c) (HbA(1c)) values and remaining beta-cell function. PATIENTS AND METHODS: We report glycemic data from a 3.5-year, open-label, observational, primary care study comparing 30 mg/day pioglitazone with 3.5 mg/day glibenclamide add-on to stable metformin monotherapy in 500 patients with type 2 diabetes. Insulin commencement was considered for patients with HbA(1c) > or = 8.0% or when vascular complications occurred. The change in HbA(1c) compared with baseline and the difference in time to failure to maintain glycemic control were calculated. RESULTS: At endpoint, HbA(1c) had decreased by 1.0% in the pioglitazone group (p < 0.005) and by 0.6% in the glibenclamide group (p < 0.05). Annual progression rates to insulin treatment were 6.6% (pioglitazone) and 16.4% (glibenclamide; p < 0.001 between-group difference). Mean weight increases of 3.5 +/- 0.42 kg in the pioglitazone group and 3.3 +/- 0.38 kg in the glibenclamide group were noted. Overall, both treatments were well tolerated. CONCLUSIONS: Pioglitazone add-on to metformin revealed significant benefits in long-term glycemic control compared with glibenclamide. This difference may be explained by a large between-group difference in HOMA-S, which was shown to correlate significantly to the change in HbA(1c). This suggests that a strategy to reduce insulin resistance to lower the burden of the beta-cell is superior to treatment with glibenclamide.     

Enhanced nimodipine bioavailability after oral administration of nimodipine with morin, a flavonoid, in rabbits

The aim of this study was to investigate the effect of morin on the bioavailability of nimodipine after administering nimodipine (15 mg/kg) orally to rabbits either co-administered or pretreated with morin (2, 10 and 20 mg/kg). The plasma concentrations of nimodipine in the rabbits pretreated with morin were increased significantly (p < 0.05 at 10 mg/kg, p < 0.01 at 20 mg/kg) compared with the control, but the plasma concentrations of nimodipine co-administered with morin were not significant. The areas under the plasma concentration-time curve (AUC) and the peak concentrations (Cmax) of the nimodipine in the rabbits pretreated with morin were significantly higher (p < 0.05 at 10 mg/kg, p < 0.01 at 20 mg/kg), but only the Cmax of nimodipine coadministered with morin 10 mg/kg was increased significantly (p < 0.05). The absolute bioavailability (A.B%) of nimodipine in the rabbits pretreated with morin was significantly (p < 0.05 at 10 mg/kg, p < 0.01 at 20 mg/kg) higher (54.1-65.0%) than the control (36.7%). The increased bioavailability of nimodipine in the rabbits pretreated with morin might have been resulted from the morin, which inhibits the effiux pump P-glycoprotein and the first-pass metabolizing enzyme by cytochrome P-450 3A4 (CYP 3A4).     

Effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide: possible role of CYP3A4 and P-glycoprotein inhibition by efonidipine

The purpose of this study was to investigate the effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide in rats. The pharmacokinetic parameters of repaglinide and blood glucose concentrations were also determined in rats after oral (0.5 mg/kg) and intravenous (0.2 mg/kg) administration of repaglinide to rats in the presence and absence of efonidipine (1 and 3 mg/kg). Efonidipine inhibited CYP3A4 activity with an IC(50) value of 0.08 μM, and efonidipine significantly inhibited P-gp activity in a concentration-dependent manner. Compared to the oral control group, efonidipine significantly increased the area under the plasma concentration-time curve (AUC(0-∞)) (P < 0.01 for 3 mg/kg) and the peak plasma concentration (C (max)) (P < 0.05 for 3 mg/kg) of repaglinide by 51.3 and 28.6%, respectively. Efonidipine also significantly (P < 0.01 for 3 mg/kg) increased the absolute bioavailability (AB) of repaglinide by 51.5% compared to the oral control group (33.6%). Moreover, efonidipine significantly increased (P < 0.05 for 3 mg/kg) the AUC(0-∞) of intravenously administered repaglinide. Consistent with these kinetic alterations, the hypoglycemic effect in the concurrent administration group was more pronounced than that in the control group (i.e., repaglinide alone) when the drug was given orally. A pharmacokinetic/dynamic model involving 2-compartment open model with inhibition in absorption/elimination and an indirect response model was apparently sufficient in estimating the concentration-time and effect-time profiles of repaglinide with or without efonidipine. Present study has raised the awareness of potential drug interactions by concomitant use of efonidipine with repaglinide, since efonidipine may alter the absorption and/or elimination of repaglinide by the inhibition of CYP3A4 and P-gp efflux pump. Therefore, the concurrent use of efonidipine with repaglinide may require a close monitoring for potential drug interactions.     

Interactions between simvastatin and troglitazone or pioglitazone in healthy subjects

Two randomized, two-period crossover studies were conducted to evaluate the effects of repeat oral dosing of troglitazone (Study I) and pioglitazone (Study II) on the pharmacokinetics of plasma HMG-CoA reductase inhibitors following multiple oral doses of simvastatin and of simvastatin on the plasma pharmacokinetics of troglitazone (Study I) in healthy subjects. In both studies, each subject received two treatments. Treatment A consisted of once-daily oral doses of troglitazone 400 mg (Study I) or pioglitazone 45 mg (Study II) for 24 days with coadministration of once-daily doses of simvastatin 40 mg (Study I) or 80 mg (Study II) on Days 15 through 24. Treatment B consisted of once-daily oral doses of simvastatin 40 mg (Study I) or 80 mg (Study II) for 10 days. In Study I, the area under the plasma concentration-time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG-CoA reductase inhibitors in subjects who received both troglitazone and simvastatin were decreased modestly (by approximately 30% for Cmax and approximately 40% for AUC), but time to reach Cmax (tmax) did not change, as compared with those who received simvastatin alone. Simvastatin, administered orally as a 40 mg tablet daily for 10 days, did not affect the AUC or tmax (p > 0.5) but caused a small but clinically insignificant increase (approximately 25%) in Cmax for troglitazone. In Study II, pioglitazone, at the highest approved dose for clinical use, did not significantly alter any of the pharmacokinetic parameters (AUC, Cmax, and tmax) of simvastatin HMG-CoA reductase inhibitory activity. For all treatment regimens, side effects were mild and transient, suggesting that coadministration of simvastatin with either troglitazone or pioglitazone was well tolerated. The modest effect of troglitazone on simvastatin pharmacokinetics is in agreement with the suggestion that troglitazone is an inducer of CYP3A. The insignificant effect of simvastatin on troglitazone pharmacokinetics is consistent with the conclusion that simvastatin is not a significant inhibitor for drug-metabolizing enzymes. The lack of pharmacokinetic effect of pioglitazone on simvastatin supports the expectation that this combination may be used safely.     

Effects of curcumin on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen, in rats: possible role of CYP3A4 and P-glycoprotein inhibition by curcumin

The effects of curcumin, a natural anti-cancer compound, on the bioavailability and pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, were investigated in rats. Tamoxifen and curcumin interact with cytochrom P450 (CYP) enzymes and P-glycoprotein, and the increase in the use of health supplements may result in curcumin being taken concomitantly with tamoxifen as a combination therapy to treat or prevent cancer. A single dose of tamoxifen was administered orally (9 mg x kg(-1)) with or without curcumin (0.5, 2.5 and 10 mg x kg(-1)) and intravenously (2mg x kg(-1)) with or without curcumin (2.5 and 10 mg x kg(-1)) to rats. The effects of curcumin on P-glycoprotein (P-gp) and CYP3A4 activity were also evaluated. Curcumin inhibited CYP3A4 activity with 50% inhibition concentration (IC50) values of 2.7 microM. In addition, curcumin significantly (P < 0.01 at 10 microM) enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp in a concentration-dependent manner. This result suggested that curcumin significantly inhibited P-gp activity. Compared to the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve (AUC(0-infinity)) and the peak plasma concentration (C(max)) of tamoxifen were significantly (P < 0.05 for 2.5 mg x kg(-1); P < 0.01 for 10 mg x kg(-1)) increased by 33.1-64.0% and 38.9-70.6%, respectively, by curcumin. Consequently, the absolute bioavailability of tamoxifen in the presence of curcumin (2.5 and 10 mg x kg(-1)) was 27.2-33.5%, which was significantly enhanced (P < 0.05 for 2.5 mg x kg(-1); P < 0.01 for 10 mg x kg(-1)) compared to that in the oral control group (20.4%). Moreover, the relative bioavailability of tamoxifen was 1.12- to 1.64-fold greater than that in the control group. Furthermore, concurrent use of curcumin significantly decreased (P < 0.05 for 10 mg x kg(-1)) the metabolite-parent AUC ratio (MR), implying that curcumin may inhibit the CYP-mediated metabolism of tamoxifen to its active metabolite, 4-hydroxytamoxifen. The enhanced bioavailability of tamoxifen by curcumin may be mainly due to inhibition of the CYP3A4-mediated metabolism of tamoxifen in the small intestine and/or in the liver and to inhibition of the P-gp efflux transporter in the small intestine rather than to reduction of renal elimination of tamoxifen, suggesting that curcumin may reduce the first-pass metabolism of tamoxifen in the small intestine and/or in the liver by inhibition of P-gp or CYP3A4 subfamily.