CYP2C9, but not CYP2C19, polymorphisms affect the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects

BACKGROUND: Although cytochrome P450 (CYP) 2C9 was thought to be the main pathway for glyburide (INN, glibenclamide) metabolism in vivo, studies in vitro indicated that CYP2C19 had a more dominant effect. This study investigated the relative influence of CYP2C9 and CYP2C19 genotypes on the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects. METHODS: Three groups of healthy male Chinese subjects (n=6 per group) were enrolled, as follows: group I, CYP2C9*1/*1 and CYP2C19 extensive metabolizers (EMs); group II, CYP2C9*1/*1 and CYP2C19 poor metabolizers (PMs); and group III, CYP2C9*1/*3 and CYP2C19 EMs. Subjects received single oral doses of 5 mg glyburide. Multiple blood samples were collected, and the plasma glyburide concentrations were determined by an HPLC method. The plasma glucose and insulin concentrations were also measured up to 2 hours after dosing. RESULTS: No significant differences in glyburide pharmacokinetics were observed between CYP2C19 EM and PM subjects who had the CYP2C9*1/*1 genotype (group I versus group II). Their respective values for area under the plasma concentration-time curve from time 0 to infinity (AUC0-infinity) and elimination half-life (t1/2) were 0.46+/-0.13 microg.h/mL versus 0.57+/- 0.11 microg.h/mL (P=.569) and 2.09+/-0.22 hours versus 2.24+/- 0.27 hours (P=.721). However, significant increases in AUC(0-infinity) (125% and 82%; P=.008 and .024, respectively) and t1/2 (71% and 60%; P=.003 and .007, respectively) were observed when CYP2C9*1/*3 subjects (group III) were compared with CYP2C9*1/*1 subjects in group I or II. Blood glucose reductions at 2 hours after dosing were 41.8%, 23.9%, and 27.7% in groups I, II, and III, respectively (P=.029), and hypoglycemia developed in 3 of 6 CYP2C9*1/*3 carriers and 2 of 12 CYP2C9*1/*1 carriers. CONCLUSION: CYP2C9, but not CYP2C19, polymorphism appears to exert a dominant influence on glyburide pharmacokinetics and pharmacodynamics in vivo. Further studies in diabetic patients with long-term dosing are warranted to confirm these findings.     

Rifampin decreases the plasma concentrations and effects of repaglinide

OBJECTIVE: To study the effects of rifampin (INN, rifampicin) on the pharmacokinetics and pharmacodynamics of repaglinide, a new short-acting antidiabetic drug. METHODS: In a randomized, two-phase crossover study, nine healthy volunteers were given a 5-day pretreatment with 600 mg rifampin or matched placebo once daily. On day 6 a single 0.5-mg dose of repaglinide was administered. Plasma repaglinide and blood glucose concentrations were measured up to 7 hours. RESULTS: Rifampin decreased the total area under the concentration-time curve of repaglinide by 57% (P < .001) and the peak plasma repaglinide concentration by 41% (P = .001). The elimination half-life of repaglinide was shortened from 1.5 to 1.1 hours (P < .01). The blood glucose decremental area under the concentration-time curve from 0 to 3 hours was reduced from 0.94 to -0.23 mmol/L x h (P < .05), and the maximum decrease in blood glucose concentration from 1.6 to 1.0 mmol/L (P < .05) by rifampin. CONCLUSIONS: Rifampin considerably decreases the plasma concentrations of repaglinide and also reduces its effects. This interaction is probably caused by induction of the CYP3A4-mediated metabolism of repaglinide. It is probable that the effects of repaglinide are decreased during treatment with rifampin or other potent inducers of CYP3A4, such as carbamazepine, phenytoin, or St John's wort.     

Rifampin induces alterations in mycophenolic acid glucuronidation and elimination: implications for drug exposure in renal allograft recipients

BACKGROUND: Exposure to mycophenolic acid (MPA) and its main metabolites (MPA 7-O-glucuronide [MPAG] and MPA acyl-glucuronide [AcMPAG]) is characterized by a large interindividual and intraindividual variability, resulting in part from variability in glucuronidation (via uridine diphosphate-glucuronosyltransferase isoforms) and excretion via multidrug resistance-associated protein 2 (MRP2). It can be hypothesized that drugs interfering with glucuronidation and excretion will alter (Ac)MPA(G) exposure. METHODS: This prospective, open-label, nonrandomized, controlled pharmacokinetic interaction study included 8 stable renal allograft recipients, all treated with mycophenolate mofetil. Rifampin (INN, rifampicin), administered once daily (600 mg/d) for 8 days, was used as the probe drug because of its known effects on both uridine diphosphate-glucuronosyltransferase activity and MRP2 transport capacity. A 12-hour pharmacokinetic time-concentration profile was assessed before rifampin administration was started, and this was repeated on the last day of rifampin administration. Total and free MPA, MPAG, and AcMPAG concentrations in plasma and urine were measured by use of HPLC with tandem mass spectrometry detection. RESULTS: Total MPA area under the plasma concentration-time curve (AUC) from 0 to 12 hours decreased significantly after rifampin coadministration (17.5% decrease [95% confidence interval (CI), 5.18%-29.9%]; P=.0234). This was mainly a result of a decrease in total MPA AUC from 6 to 12 hours (32.9% decrease [95% CI, 15.4%-50.4%]; P=.0078), representing decreased enterohepatic recirculation. Free MPA AUC from 6 to 12 hours decreased significantly, by 22.4% (95% CI, 4.71%-49.5%; P=.0391). Total MPAG and AcMPAG AUC from 0 to 12 hours increased by 34.4% (95% CI, 13.5%-55.4%; P=.0156) and 193% (95% CI, 30.3%-355%; P=.0078) respectively. Urinary recovery of MPAG and AcMPAG increased significantly (P=.0078), but renal clearance of these glucuronides did not change after rifampin coadministration. CONCLUSION: This study demonstrates an interaction between mycophenolate mofetil and rifampin, which is a result of induction of MPA glucuronidation and possibly also rifampin-associated alterations in MRP2-mediated transport of MPAG and AcMPAG. This interaction should be taken into account when rifampin or other drugs influencing pregnane X receptor activity are coadministered with mycophenolate mofetil.     

The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron

BACKGROUND: Ondansetron is an antiemetic agent metabolized by cytochrome P450 (CYP) enzymes. Rifampin (INN, rifampicin) is a potent inducer of CYP3A4 and some other CYP enzymes. We examined the possible effect of rifampin on the pharmacokinetics of orally and intravenously administered ondansetron. METHODS: In a randomized crossover study with 4 phases and a washout of 4 weeks, 10 healthy volunteers took either 600 mg rifampin (in 2 phases) or placebo (in 2 phases) once a day for 5 days. On day 6, 8 mg ondansetron was administered either orally (after rifampin and placebo) or intravenously (after rifampin and placebo). Ondansetron concentrations in plasma were measured up to 12 hours. RESULTS: The mean total area under the plasma concentration-time curve [AUC(0-infinity)] of orally administered ondansetron after rifampin pretreatment was reduced by 65% compared with placebo (P < .001). Rifampin decreased the peak plasma concentration of oral ondansetron by about 50% (from 27.2+/-3.0 to 13.8+/-1.5 ng/mL [mean +/- SEM]; P < .001]) and the elimination half-life (t1/2) by 38% (P < .01). The bioavailability of oral ondansetron was reduced from 60% to 40% (P < .01) by rifampin. The clearance of intravenous ondansetron was increased 83% (from 440+/-38.4 to 805+/-44.6 mL/min [P < .001]) by rifampin. Rifampin reduced the t1/2 of intravenously administered ondansetron by 46% (P < .001) and the AUC(0-infinity) by 48% (P < .001). CONCLUSIONS: Rifampin considerably decreases the plasma concentrations of ondansetron after both oral and intravenous administration. The interaction is most likely the result of induction of the CYP3A4-mediated metabolism of ondansetron. Concomitant use of rifampin or other potent inducers of CYP3A4 with ondansetron may result in a reduced antiemetic effect, particularly after oral administration of ondansetron.     

Transfer of glyburide and glipizide into breast milk

OBJECTIVE: To determine if glyburide and glipizide are excreted into breast milk and if breast-feeding from women taking these drugs causes infant hypoglycemia. RESEARCH DESIGN AND METHODS: We studied eight women who had received a single oral dose of 5 or 10 mg glyburide. Drug concentrations were measured in maternal blood and milk for 8 h after the dose. In a separate study, five women were given a daily dosage (5 mg/day) of glyburide or glipizide, starting on the first postpartum day. Maternal blood and milk drug concentrations and infant blood glucose were measured 5-16 days after delivery. RESULTS: In the single-dose glyburide study, the mean maximum theoretical infant dose (MTID) as a percent of the weight-adjusted maternal dose (WAMD) was <1.5 and <0.7% for the 5- and 10-mg doses, respectively. For the five women taking daily dosages, the mean MTID as a percent of the WAMD was <28% for glyburide and <27% for glipizide. The high estimates were due to the insensitivity of the assay. Neither glyburide nor glipizide were detected in breast milk in either study and blood glucose was normal in the three infants (one glyburide and two glipizide) who were wholly breast-fed when the drug concentrations were at steady state. CONCLUSIONS: Neither glyburide nor glipizide were detected in breast milk, and hypoglycemia was not observed in the three nursing infants. Both agents, at the doses tested, appear to be compatible with breast-feeding.     

Effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide

OBJECTIVE: Our objective was to investigate the effect of rifampin (INN, rifampicin) on the pharmacokinetics and pharmacodynamics of gliclazide, a sulfonylurea antidiabetic drug. METHOD: In a randomized 2-way crossover study with a 4-week washout period, 9 healthy Korean subjects were treated once daily for 6 days with 600 mg rifampin or with placebo. On day 7, a single dose of 80 mg gliclazide was administered orally. Plasma gliclazide, blood glucose, and insulin concentrations were measured. RESULTS: Rifampin decreased the mean area under the plasma concentration-time curve for gliclazide by 70% (P <.001) and the mean elimination half-life from 9.5 to 3.3 hours (P <.05). The apparent oral clearance of gliclazide increased about 4-fold after rifampin treatment (P <.001). A significant difference in the blood glucose response to gliclazide was observed between the placebo and rifampin phases. CONCLUSION: The effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide suggests that rifampin affects the disposition of gliclazide in humans, possibly by the induction of cytochrome P450 2C9. Concomitant use of rifampin with gliclazide can considerably reduce the glucose-lowering effects of gliclazide.     

Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone

BACKGROUND: Trimethoprim is a relatively selective inhibitor of the cytochrome P450 (CYP) 2C8 enzyme in vitro. Rifampin (INN, rifampicin) is a potent inducer of several CYP enzymes, and in vitro studies have suggested that it also induces CYP2C8. OBJECTIVE: Our aims were to investigate possible effects of trimethoprim and rifampin on CYP2C8 activity by use of rosiglitazone, a thiazolidinedione antidiabetic drug metabolized primarily by CYP2C8, as an in vivo probe. METHODS: Two separate randomized crossover studies with 2 phases were conducted. In study 1, 10 healthy volunteers took 160 mg trimethoprim or placebo orally twice daily for 4 days. On day 3, they ingested a single 4-mg dose of rosiglitazone. In study 2, 10 healthy volunteers took 600 mg rifampin or placebo orally once daily for 5 days. On day 6, they ingested a single 4-mg dose of rosiglitazone. In both studies, plasma rosiglitazone and N -desmethylrosiglitazone concentrations were measured for up to 48 hours. Results In study 1, trimethoprim raised the area under the plasma rosiglitazone concentration-time curve [AUC(0- infinity )] by 37% (range, 16% to 51%; P <.0001) and the peak plasma rosiglitazone concentration (C max ) by 14% (range, -3% to 38%; P =.0014). The elimination half-life (t 1/2 ) of rosiglitazone was prolonged from 3.8 to 4.8 hours ( P =.0013). Trimethoprim reduced the formation of N -desmethylrosiglitazone. In study 2, rifampin reduced the AUC(0- infinity ) and C max of rosiglitazone by 54% (range, 46% to 63%; P <.0001) and 28% (range, 2% to 56%; P =.0003), respectively. The t 1/2 of rosiglitazone was shortened from 3.8 to 1.9 hours ( P <.0001). Rifampin increased the formation of N -desmethylrosiglitazone. CONCLUSIONS: Trimethoprim raises and rifampin reduces the plasma concentrations of rosiglitazone by inhibiting and inducing, respectively, the CYP2C8-catalyzed biotransformation of rosiglitazone.     

Benefits and risks with glyburide and glipizide in elderly NIDDM patients.

OBJECTIVE--To compare the efficacy, benefits, and risks of glyburide and glipizide in elderly patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS--Twenty-one elderly outpatients (mean age 70 yr) were treated for 8 wk, after being dose-titrated to achieve a fasting plasma glucose (FPG) concentration of less than 7.8 mM with glyburide or glipizide in a randomized crossover trial. FPG and postprandial plasma glucose, serum C-peptide, and HbA1c levels were measured. In 13 patients, self-monitoring of blood glucose (SMBG) with a memory meter was performed seven times per week. RESULTS--Glipizide (11.9 mg) and glyburide (8.4 mg) produced similar fasting and postprandial plasma glucose and HbA1c concentrations. No significant differences in basal or stimulated C-peptide levels were detected. Despite a few patient reports of hypoglycemia, a high incidence of SMBG readings less than 4.5 mM was attributed to the use of both drugs. CONCLUSIONS--Both treatments proved effective for glycemic control; however, both second-generation sulfonylureas are associated with a significant risk of hypoglycemia in elderly NIDDM patients. The proper use of sulfonylureas in this population should include close surveillance of ambulatory glucose monitoring and intensive and repeated patient education about the risks of hypoglycemia.     

Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers

BACKGROUND: Glyburide (INN, glibenclamide) is a second-generation sulfonylurea antidiabetic agent with high potency. We hypothesized that glyburide may be a substrate of cytochrome P450 2C9 (CYP2C9), an enzyme that has two low-activity amino acid variants-Arg144Cys (CYP2C9*2) and Ile359Leu (CYP2C9*3). We explored the impact of these polymorphisms on glyburide pharmacokinetics and the effects on insulin and glucose concentrations. METHODS: Twenty-one healthy volunteers who represented all possible combinations of the two variant alleles were studied (genotypes CYP2C9*1/*1, *1/*2, *2/*2, *1/*3, *2/*3, and *3/*3 ). They received a single oral dose of 3.5 mg glyburide followed by 75 g glucose at 1, 4.5, and 8 hours after administration of glyburide. Glyburide was quantified in plasma by reversed-phase HPLC. Venous blood concentrations of glyburide, insulin, and glucose were analyzed with a population pharmacokinetic-pharmacodynamic model by use of NONMEM statistical software. RESULTS: Pharmacokinetics of glyburide depended significantly on CYP2C9 genotypes. In homozygous carriers of the genotype *3/*3, total oral clearance was less than half of that of the wild-type genotype *1/*1 (P <.001). Correspondingly, insulin secretion measured within 12 hours after glyburide ingestion was higher in carriers of the genotype *3/*3 compared with the other genotypes (P =.028), whereas the differences in glucose concentrations were not significant. CONCLUSIONS: Carriers of the CYP2C9 variant *3 had decreased oral clearances of glyburide. This confirms that glyburide is metabolized by CYP2C9. Corresponding differences in insulin plasma levels indicated that dose adjustment based on CYP2C9 genotype may improve antidiabetic treatment.     

Rifampin markedly decreases plasma concentrations of praziquantel in healthy volunteers

BACKGROUND AND OBJECTIVE: Praziquantel is extensively metabolized by the hepatic cytochrome P450 (CYP) enzymes. The CYP3A isoforms are likely to be major enzymes responsible for praziquantel metabolism. Rifampin (INN, rifampicin), a potent enzyme inducer of CYP-mediated metabolism (especially CYP2C9, CYP2C19, and CYP3A4), is known to markedly decrease plasma concentrations and effects of a number coadministered drugs. The aim of this investigation was to study the possible pharmacokinetic interaction between rifampin and praziquantel. METHODS: An open, randomized, 2-phase crossover design was used in each study of single or multiple doses. In the single-dose study, 10 healthy Thai male volunteers ingested single doses of 40 mg/kg praziquantel alone (phase 1) or after pretreatment with 600 mg of oral rifampin once daily for 5 days (phase 2). In the multiple-dose study, all participants received multiple doses of 25 mg/kg praziquantel alone (phase 1) or after 5-day pretreatment with 600 mg of oral rifampin once daily (phase 2). Plasma concentrations of praziquantel in each phase were determined by the HPLC method. RESULTS: In the single-dose study, rifampin decreased plasma praziquantel concentrations to undetectable levels in 7 of 10 subjects, whereas praziquantel concentrations were reduced by rifampin to undetectable levels in 5 of 10 subjects in the multiple-dose study. In 3 subjects with measurable concentrations in the single-dose study, rifampin significantly decreased the mean maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from 0 to 24 hours [AUC(0-24)] of praziquantel by 81% (P <.05) and 85% (P <.01), respectively, whereas rifampin significantly decreased the mean C(max) and AUC(0-24) of praziquantel by 74% (P <.05) and 80% (P <.01), respectively, in 5 subjects with measurable concentrations in the multiple-dose study. The mean C(max) and AUC(0-24) of praziquantel in subjects whose praziquantel concentrations could not be detected in the single-dose study (7 subjects) after rifampin pretreatment were reduced by approximately 99% (P <.001) and 94% (P <.001), respectively, and in the multiple-dose study (5 subjects), they were reduced by 98% (P <.05) and 89% (P <.01), respectively. CONCLUSIONS: Rifampin greatly decreased plasma concentrations of single and multiple oral doses of praziquantel to levels lower than that of the minimum therapeutic concentration. Because praziquantel and rifampin are widely used in the treatment of liver flukes (Opisthorchis viverrini) and Mycobacterium tuberculosis, respectively, in Thailand and in some other countries in southeast Asia, the possibility of one drug influencing the pharmacokinetics of the other must be considered. Therefore simultaneous use of rifampin and praziquantel must be avoided in medical practice to optimize the therapeutic efficacy of praziquantel.     

Elucidating rifampin's inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite

The effects of single doses of intravenous (IV) ciprofloxacin and rifampin and of multiple doses of rifampin on glyburide exposure and blood glucose levels were investigated in nine healthy volunteers. A single IV dose of rifampin significantly increased the area under the concentration-time curve (AUC) of glyburide and its metabolite. Blood glucose levels were significantly lower than those observed after dosing with glyburide alone. Multiple doses of rifampin induced an increase in liver enzyme levels, leading to a marked decrease in glyburide exposure and blood glucose levels. When IV rifampin was administered after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect; however, the relative changes in AUC for glyburide and its hydroxyl metabolite were similar to those seen under noninduced conditions. The studies reported here demonstrate how measurements of the levels of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and in characterizing enzymatic vs. transporter mechanisms.     

The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive

BACKGROUND: Rifampin (INN, rifampicin), a CYP34A inducer, results in significant interactions when coadministered with combination oral contraceptives that contain norethindrone (INN, norethisterone) and ethinyl estradiol (INN, ethinylestradiol). Little is known about the effects of rifabutin, a related rifamycin. OBJECTIVES AND METHODS: The relative effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 microg ethinyl estradiol/1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. RESULTS: Rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] of ethinyl estradiol and the mean AUC(0-24) of norethindrone. Rifabutin significantly decreased the mean AUC(0-24) of ethinyl estradiol and the mean AUC(0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC(0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. CONCLUSION: In this study, rifampin (600 mg daily) was a more significant inducer of ethinyl estradiol and norethindrone clearance than rifabutin (300 mg daily), but neither agent reversed the suppression of ovulation caused by oral contraceptives. The carefully monitored oral contraceptive administration and the limited exposure to rifamycins may restrict the application of this study to clinical situations.     

Comparison of pharmacokinetics, metabolic effects and mechanisms of action of glyburide and glipizide during long-term treatment

Fourteen non-insulin-dependent diabetic (NIDDM) patients continued their previous medication (7 on glyburide, 7 on glipizide) for 6 mo, after which they switched to the alternate treatment for another 6 mo. The treatment periods were followed by 1 mo of placebo. The sulfonylurea dose was increased to achieve fasting plasma glucose levels less than 9 mM or to a total maximum daily dose of 25 mg. The mean final doses of glyburide (14.7 +/- 2.4 mg/day) and glipizide (15.2 +/- 2.2 mg/day) were similar. Postprandial (postdose) glipizide levels were higher than those of glyburide, whereas fasting (predose) glyburide concentrations were higher than those of glipizide. Both treatments improved glucose control by 25% compared with placebo. Glipizide therapy evoked higher postprandial insulin concentrations than did glyburide, whereas basal insulin concentrations were higher during glyburide. Insulin sensitivity, assessed by an insulin tolerance test, was more improved with glyburide than with glipizide. In conclusion, overall glucose control is similarly improved by glyburide and glipizide. However, glipizide amplifies the plasma insulin response to meals more than glyburide, whereas glyburide enhances basal insulin secretion more than glipizide. Both pharmacokinetic and pharmacodynamic factors may contribute to these differences.     

Glyburide versus glipizide in the treatment of patients with non-insulin-dependent diabetes mellitus.

Thirty-four adults with non-insulin-dependent diabetes mellitus were randomly assigned to receive either oral glyburide or oral glipizide in a multicenter comparative trial. Fasting blood glucose and hemoglobin A1c (HbA1c) were assessed at the beginning of the titration phase, the beginning of maintenance therapy, and the end of maintenance therapy. Maintenance therapy lasted approximately 3 months. The initial mean total dose of glyburide (5.4 mg) was significantly lower than that of glipizide (10.6 mg) (P = 0.04) and remained significantly lower at the beginning of maintenance therapy (7.8 mg versus 15.3 mg; P < 0.01) and at the end of the trial (10 mg versus 16.8 mg; P = 0.05). Although significant differences were not detected for fasting blood glucose or HbA1c, patients received higher total doses of glipizide compared with glyburide at the middle and final evaluations to maintain the fasting blood glucose between 3.9 and 10 mmol/L and HbA1c at < 9%. No serious adverse reactions were observed in any patient. These results indicate that doses of glipizide required to maintain blood glucose between 3.9 and 10 mmol/L and HbA1c at < 9% increased over time. Seventy-five percent of patients receiving glyburide were controlled with once-daily dosing compared with 29.4% of those treated with glipizide. Both glyburide and glipizide provide safe and effective treatment for patients with non-insulin-dependent diabetes mellitus, but more patients will benefit from once-daily therapy with glyburide.     

Cyclosporine markedly raises the plasma concentrations of repaglinide

BACKGROUND AND OBJECTIVE: Repaglinide is an antidiabetic drug metabolized by cytochrome P450 (CYP) 2 C 8 and 3A4, and it appears to be a substrate of the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1). We studied the effects of cyclosporine (INN, ciclosporin), an inhibitor of CYP3A4 and OATP1B1, on the pharmacokinetics and pharmacodynamics of repaglinide. METHODS: In a randomized crossover study, 12 healthy volunteers took 100 mg cyclosporine or placebo orally at 8 pm on day 1 and at 8 am on day 2. At 9 am on day 2, they ingested a single 0.25-mg dose of repaglinide. Concentrations of plasma and urine repaglinide and its metabolites (M), blood cyclosporine, and blood glucose were measured for 12 hours. The subjects were genotyped for single-nucleotide polymorphisms in CYP2C8, CYP3A5, SLCO1B1 (encoding OATP1B1), and ABCB1 (P-glycoprotein). The effect of cyclosporine on repaglinide metabolism was studied in human liver microsomes in vitro. RESULTS: During the cyclosporine phase, the mean peak repaglinide plasma concentration was 175% (range, 56%--365%; P=.013) and the total area under the plasma concentration-time curve [AUC0--infinity] was 244% (range, 119%--533%; P<.001) of that in the placebo phase. The amount of unchanged repaglinide and its metabolites M2 and M4 excreted in urine were raised 2.7--fold, 7.5--fold, and 5.0--fold, respectively, by cyclosporine (P<.001). The amount of M1 excreted in urine remained unchanged, but cyclosporine reduced the ratio of M1 to repaglinide by 62% (P<.001). Cyclosporine had no significant effect on the elimination half-life or renal clearance of repaglinide. Although the mean blood glucose-lowering effect of repaglinide was unaffected in this low-dose study with frequent carbohydrate intake, the subject with the greatest pharmacokinetic interaction had the greatest increase in blood glucose-lowering effect. The effect of cyclosporine on repaglinide AUC0-infinity was 42% lower in subjects with the SLCO1B1 521TC genotype than in subjects with the 521TT (reference) genotype (P=.047). In vitro, cyclosporine inhibited the formation of M1 (IC50 [concentration of inhibitor to cause 50% inhibition of original enzyme activity], 0.2 micromol/L) and M2 (IC50, 4.3 micromol/L) but had no effect on M4. CONCLUSIONS: Cyclosporine raised the plasma concentrations of repaglinide, probably by inhibiting its CYP3A4-catalyzed biotransformation and OATP1B1-mediated hepatic uptake. Coadministration of cyclosporine may enhance the blood glucose-lowering effect of repaglinide and increase the risk of hypoglycemia.     

Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide

BACKGROUND AND OBJECTIVE: The antidiabetic repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and CYP3A4. Telithromycin, an antimicrobial agent, inhibits CYP3A4 in vitro and in vivo. Montelukast, an antiasthmatic drug, is a potent inhibitor of CYP2C8 in vitro. We studied the effects of telithromycin, montelukast, and the combination of telithromycin and montelukast on the pharmacokinetics and pharmacodynamics of repaglinide. METHODS: In a randomized 4-phase crossover study, 12 healthy volunteers received 800 mg telithromycin, 10 mg montelukast, both telithromycin and montelukast, or placebo once daily for 3 days. On day 3, they ingested a single 0.25-mg dose of repaglinide. Plasma and urine concentrations of repaglinide and its metabolites M1, M2, and M4, as well as blood glucose concentrations, were measured for 12 hours. RESULTS: Telithromycin alone raised the mean peak plasma repaglinide concentration to 138% (range, 91%-209%; P = .006) and the total area under the plasma concentration-time curve from 0 hours to infinity [AUC0-infinity] of repaglinide to 177% (range, 125%-257%; P < .001) of control (placebo). Telithromycin reduced the AUC0-infinity ratio of the metabolite M1 to repaglinide by 68% (P < .001) and the urinary excretion ratio of M1 to repaglinide by 77% (P = .001). In contrast to previous estimates based on in vitro CYP2C8 inhibition data, montelukast had no significant effect on the pharmacokinetics of repaglinide or its metabolites and did not significantly alter the effect of telithromycin on repaglinide pharmacokinetics. Telithromycin, unlike montelukast, lowered the maximum blood glucose concentration (P = .002) and mean blood glucose concentration from 0 to 3 hours (P = .008) after repaglinide intake, as compared with placebo. CONCLUSIONS: Telithromycin increases the plasma concentrations and blood glucose-lowering effect of repaglinide by inhibiting its CYP3A4-catalyzed biotransformation and may increase the risk of hypoglycemia. Unexpectedly, montelukast has no significant effect on repaglinide pharmacokinetics, suggesting that it does not significantly inhibit CYP2C8 in vivo. The low free fraction of montelukast in plasma may explain the lack of effect on CYP2C8 in vivo, despite the low in vitro inhibition constant, highlighting the importance of incorporating plasma protein binding to interaction predictions.     

Gemfibrozil greatly increases plasma concentrations of cerivastatin

BACKGROUND: Concomitant use of gemfibrozil with statins, particularly with cerivastatin, increases the risk of rhabdomyolysis, but the mechanism of this potentially fatal drug interaction remains unclear. Our aim was to study the effect of gemfibrozil on cerivastatin pharmacokinetics. METHODS: In a randomized, double-blind crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo twice daily for 3 days. On day 3, each subject ingested a single 0.3-mg dose of cerivastatin. Plasma concentrations of cerivastatin, its metabolites, and gemfibrozil were measured up to 24 hours. RESULTS: During gemfibrozil treatment, the area under the plasma concentration-time curve [AUC(0-infinity)] of parent cerivastatin was on average 559% (range, 138% to 995%; P =.0002) and the peak concentration in plasma was 307% (138% to 809%; P =.0019) of the corresponding values in the placebo phase. Gemfibrozil increased the AUC(0-infinity) of cerivastatin lactone, on average, to 440% (94% to 594%; P =.0024) and that of metabolite M-1 to 435% (216% to 802%; P =.0002) of the control (placebo) values, whereas the AUC(0-24) of metabolite M-23 was decreased to 22% (11% to 74%; P =.0017). CONCLUSIONS: Gemfibrozil greatly increases plasma concentrations of cerivastatin, cerivastatin lactone, and metabolite M-1, whereas the level of metabolite M-23 is markedly reduced by gemfibrozil. Gemfibrozil therefore inhibits the formation of M-23, which is thought to be dependent on CYP2C8. The increased exposure to cerivastatin in the presence of gemfibrozil may explain the high incidence of myopathy observed with this combination, although the role of pharmacodynamic interactions between these 2 agents cannot be excluded.     

The sulfonylurea glyburide induces impairment of glucagon and growth hormone responses during mild insulin-induced hypoglycemia.

OBJECTIVE: The sulfonylurea (SU) glyburide may cause severe and prolonged episodes of hypoglycemia. We aimed at investigating the impact of glyburide on glucose counterregulatory hormones during stepwise hypoglycemic clamp studies. RESEARCH DESIGN AND METHODS: We performed stepwise hypoglycemic clamp studies in 16 healthy volunteers (7 women and 9 men aged 44 +/- 10 years). We investigated counterregulatory hormonal and symptom responses at arterialized venous plasma glucose levels (PG) of 3.8, 3.2, and 2.6 mmol/l, comparing 10 mg glyburide orally and placebo in a double-blind, randomized crossover fashion. RESULTS: The increase in plasma glucagon with time from PG = 3.8 onward was smaller for glyburide than for placebo (P = 0.014). Plasma glucagon area under the curve (AUC)(60-180) was lower after glyburide than after placebo (1,774 +/- 715 vs. 2,161 +/- 856 pmol. l(-1). min, P = 0.014). From PG = 3.8 onward, plasma growth hormone (GH) levels with placebo were nearly two times (1.9 [95% CI 1.2-2.9]) as high as with glyburide (P = 0.011). AUC(60-180) for GH was lower after glyburide than after placebo (geometric mean [range] 665 [356-1,275] and 1,058 [392-1,818] mU. l(-1). min, respectively; P = 0.04). No significant differences were observed for plasma cortisol, epinephrine and norepinephrine, or incremental symptom scores. CONCLUSIONS: The SU glyburide induces multiple defects in glucose counterregulatory hormonal responses, notably decreases in both glucagon and GH release.     

Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites

BACKGROUND: The pharmacokinetic interactions of the widely used statin atorvastatin with fibrates and enzyme inducers are not known. Therefore we studied the effects of rifampin (INN, rifampicin) and gemfibrozil on the pharmacokinetics of atorvastatin. METHODS: Two randomized crossover studies were conducted. In study 1, 10 healthy volunteers took 600 mg rifampin or placebo once daily for 5 days. On day 6, they ingested a single 40-mg dose of atorvastatin. In study 2, 10 healthy volunteers took 600 mg gemfibrozil or placebo twice daily for 5 days. On day 3, they ingested a single 20-mg dose of atorvastatin. Plasma concentrations of atorvastatin (in nanograms per milliliter) and its metabolites (in arbitrary units) were measured by liquid chromatography-tandem mass spectrometry up to 48 to 72 hours after dosing. RESULTS: Rifampin reduced the total area under the plasma concentration-time curve (AUC) of unchanged atorvastatin (acid) by 80% (95% confidence interval [CI], 73% to 84%; P < .001), that of the active metabolites 2-hydroxyatorvastatin acid by 43% (95% CI, 29% to 51%; P < .001) and 4-hydroxyatorvastatin acid by 81% (95% CI, 74% to 84%; P < .001), and that of their lactones by 93% (95% CI, 90% to 95%), by 61% (95% CI, 50% to 69%), and by 76% (95% CI, 70% to 81%), respectively (P < .001). The peak plasma concentration of 2-hydroxyatorvastatin acid was increased by 68% (95% CI, 21% to 127%; P = .005) by rifampin. Rifampin shortened (P < .001) the half-lives of atorvastatin (by 74%; 95% CI, 67% to 81%) and its metabolites, for example, atorvastatin lactone (by 82%; 95% CI, 80% to 85%) and 2-hydroxyatorvastatin acid (by 70%; 95% CI, 64% to 78%). Gemfibrozil increased the AUC of atorvastatin (by 24%; 95% CI, -1% to 50%; P =.059), 2-hydroxyatorvastatin acid (by 51%; 95% CI, 28% to 70%; P < .001) and its lactone (by 29%; 95% CI, 13% to 53%; P =.003), and 4-hydroxyatorvastatin acid (by 82%; 95% CI, 60% to 126%; P < .001) and its lactone (by 28%; 95% CI, 15% to 51%; P =.001). The half-lives of atorvastatin and its lactone metabolites were slightly shortened by gemfibrozil (P < .05). CONCLUSIONS: Rifampin markedly decreases and gemfibrozil moderately increases the plasma concentrations of atorvastatin and its metabolites. It is advisable to increase the dosage of atorvastatin and preferable to administer it in the evening to guarantee adequate concentrations during the nighttime rapid cholesterol synthesis when rifampin or other potent inducers of cytochrome P450 3A4 are coadministered. Care is warranted, and only low doses of atorvastatin should be used if coadministration with gemfibrozil is needed.     

Evaluation of glipizide and glyburide in a health maintenance organization.

OBJECTIVE: To determine if there was a difference in the long-term glycemic control, average daily dose, and cost of therapy in patients with noninsulin-dependent diabetes mellitus (NIDDM) treated with glyburide and glipizide in a health maintenance organization (HMO). DESIGN: Retrospective evaluation of medical and pharmacy records. SETTING: Multispecialty group practice HMO. PATIENTS: 140 NIDDM patients being treated with either glyburide (n = 70) or glipizide (n = 70) were randomly selected from the populations of patients receiving either drug using computerized pharmacy records. MAIN OUTCOME MEASURE: Mean daily doses and blood glucose measurements (fasting blood glucose, random blood glucose, hemoglobin A1C) were stratified in 3-month periods from the time the drug therapy was started or the patient first presented to the clinic for a total of 18 months. Long-term glycemic control was defined as fasting blood glucose less than 8.33 mmol/L (150 mg/dL). RESULTS: The groups were comparable with regard to age (53.4 y glyburide, 56.7 y glipizide), gender (43 M:27 F glyburide, 47 M:23 F glipizide), race (38 W/16 B/16 H glyburide, 45 W/16 B/9 H glipizide), concurrent medical conditions, adverse effects, and compliance. Long-term glycemic control was similar in both groups. Although the number of subjects who were controlled (by definition) tended to be greater in the glyburide group, no clinical or statistical difference was found. There was no statistical difference in mean daily dose between the ethnic groups, but the small numbers preclude further analysis. The glipizide group had a larger percentage increase in dose within the first year than did the glyburide group; however, the percentage increase from the 3-month dose was similar after 18 months (22.7 percent glyburide, 27.5 percent glipizide.) Average daily cost of therapy, based on mean daily dose, was slightly lower for glyburide-treated patients. CONCLUSIONS: If glycemic control is similar with glyburide and glipizide, as seen in this study, economic considerations regarding choice of therapy and formulary inclusion may be appropriate.