Pharmacokinetics Of Digoxin Research Articles

Pharmacology of inotropic agents in infants and children

Inotropic agents are drugs which increase the stroke work of the heart at a given pre-load and after-load. All of these agents work through a final common pathway involving the modulation of calcium interactions with various myocardial contractile proteins. The agents employed with pediatric patients include the cardial glycosides, catecholamine β-agonists and the selective phosphodiesterase III inhibitors. Digoxin is the prototypic cardiac glycoside which has a long history of safe and effective use in infants and children. Its utility in improving right ventricular dysfunction in patients with cor pulmonale leading to biventricular dysfunction makes it ideally suited to the pediatric population. Monitoring digoxin pharmacokinetics in infants is confounded by the presence of an endogenous digoxin-like substance. Nevertheless, the drug is well suited for subacute and chronic myocardial support. In contrast, the catecholamines are the drugs of choice for acute intervention. Their pharmacokinetics permit rapid dosing titration. In infants and children the greatest experience has been accrued with dopamine, a mixed α- and β-agonist but both epinephreine and norepinephrine are being used with increasing frequency as the need for drugs with increased potency and pressor activity becomes more common. The phosphodiesterase inhibitors amrinone and milrinone are the newest additions to our therapeutic armamentarium. In addition to their modest inotropic effects, amrinone and to a greater extent, milrinone offer significant pulmonary vasodilatation as part of their therapeutic package. These effects occur with little or any impact on myocardial oxygen consumpton while their lusitropic effects enhance relaxation in hypertrophied ventricular muscle. Of the two agents milrinone is probably preferred due to its greater therapeutic index and shorter elimination half-life. All of these agents remain important tools in the care of critically ill infants and children. The rational use of these drugs based upon their pharmacokinetic and pharmacodynamic properties is essential to achieve their optimal effects.

Pharmacokinetics of intravenously administered digoxin and histopathological picture in rabbits with experimental bile duct obstruction

This study aimed to examine the effect of obstructive cholestasis on the pharmacokinetics of digoxin. Eighteen male rabbits were randomly ascribed to the two study groups: the sham-operated control group and the examined group — with common and cystic bile duct ligations. Digoxin was administered intravenously as a single dose of 0.02 mg/kg, and blood samples were withdrawn for up to 24 h. Digoxin concentrations were determined by the FPIA method. The pharmacokinetic parameters were calculated using a noncompartmental analysis. During the whole observation period the blood serum concentrations of digoxin were statistically higher in animals with obstructive cholestasis versus the controls. A significant increase in the area under the plasma concentration–time curve, decrease in the total body clearance and in the volume of distribution on the 6th day after the bile ducts ligation as compared to the sham-operated controls, were observed. The obtained results suggest an impaired elimination of digoxin in obstructive cholestasis in rabbits.

The population pharmacokinetics of digoxin in dogs with heart disease.

Clinical monitoring of digoxin plasma concentration is recommended because of both a large inter-animal variation in digoxin pharmacokinetics and the small ratio of toxic/therapeutic concentrations. Digoxin concentration data from clinical therapeutic drug monitoring (TDM) are used to adapt dosage regimes. Hierarchical mixed effects modeling of TDM data can be used to identify factors that are covariables for pharmacokinetic model parameters. Knowledge of such pharmacokinetic model covariables may help to improve dose calculations and predictions and can also help to understand the pharmacodynamics of drug action and toxicity. Such models have been developed for digoxin in humans (Sheiner et al., 1977). The pharmacokinetics of digoxin in healthy dogs has been described previously (Button et al., 1980b) and dosage regimes have been examined in dogs with induced (Button et al., 1980a) or naturally occurring congestive heart failure (Tobias et al., 1989). These previous studies showed that dose adjustments made according to assumed covariables for digoxin pharmacokinetics did not accurately achieve the desired plasma concentrations in individual animals (Tobias et al., 1989). Individualized dosage regimes using TDM are necessary to achieve desired plasma digoxin concentration in dogs (Button et al., 1980a). We applied hierarchical mixed effects modeling to examine the pharmacokinetics of digoxin in 161 cases with naturally occurring heart disease in dogs. Of these, 32 were examined prospectively and 129 retrospectively. We aimed to describe the pharmacokinetics of digoxin in dogs with heart disease and to identify covariables, which could be used to predict an individual dog’s digoxin pharmacokinetics. Samples for digoxin analysis were taken at steady-state, after known but varying doses, dose intervals and dose-to-sample intervals, from routine clinical TDM cases. These samples were analyzed using commercial kit RIA or EMIT assays. Covariable data collected included serum creatinine, serum potassium, body weight (kg) x (x=0.75, 1), estimated body surface area, age and the formulation administered (Lanoxin tablets or pediatric elixir, Glaxo Wellcome). A one compartment open pharmacokinetic model for oral administration was applied to the data using proprietary software (PPharm v 1.51, Innaphase, France). Initial modeling identified two distinct populations of cases, one with a markedly slower absorption rate constant (ka) than the other (Fig. 1). Analysis for k-means clustering based on Euclidean differences identified two populations, one of 19 cases and one of 142 cases (Systat v 8.0, SPSS Inc. Chicago, IL, USA). The means of the two sample populations for ka differed statistically using Student’s t-test (PB0.01) (Table 1.). No correlation was identified between the 19 slow absorbing cases and any known covariable, including dose formulation (Fig. 1). All 19 slow absorbers were from the 32 cases (19/32=59%) which had been admitted to the hospital, a stressful event, within 2 h prior to dosing: in contrast, the remaining 129/142 (91%) cases had been dosed at home prior to sample collection. Acute stress has been associated with release of corticotrophin releasing factor (CRF) and intracerebroventricular infusion of CRF has been shown to delay total gastric emptying in dogs (Lee & Sarna, 1997). Therefore, we hypothesize that the slower absorption of orally administered digoxin was due to delayed gastric emptying in 59% cases admitted to hospital for dosing. Stress and pain have previously been shown to alter drug absorption and metabolism (Jamali & Kunz-Dober, 1999). Knowledge of a delay in absorption of drugs administered to patients by the oral route at the time of hospitalization, if confirmed, would influence selection of the route of drug administration for such patients. Multimodal populations violate the assumption of normal/ log-normal population distribution for parametric population pharmacokinetic analysis. Therefore, all 19 cases identified to have a low ka were deleted from further analyses. For the remaining 142 cases the number of observations per subject

Population pharmacokinetics of digoxin in Korean patients.

Digoxin possesses a narrow therapeutic index and shows a large inter-patient pharmacokinetic variability. The purpose of this study was to develop a population model for the pharmacokinetics of digoxin in Korean patients. Plasma concentrations of digoxin after multiple administration at varying dosing schedules in Korean patients were used for population modeling. Data analysis was performed with the P-Pharm software. The data were best fitted by a one-compartment model. The effect of demographic and clinical factors like sex, age, weight, disease state, and renal function on the pharmacokinetic parameters of digoxin was investigated. The study indicated that the clearance of digoxin was influenced by creatinine clearance, while body weight and creatinine clearance were the covariates for its volume of distribution. The population mean estimates for CL and V were 4.4 l/h and 535 l, respectively. Absorption rate constant was lower in females and in the presence of concomitant drug treatment. A population pharmacokinetic model for the digoxin pharmacokinetics in a section of Korean patients was developed. The relationships between the pharmacokinetic parameters and the demographic data and the patient-specific covariates were established.

Drug interaction studies with repaglinide: repaglinide on digoxin or theophylline pharmacokinetics and cimetidine on repaglinide pharmacokinetics.

Drug interaction studies were carried out to ensure that hypoglycemia due to inhibition of repaglinide elimination or chronic hyperglycemia due to inhibition of repaglinide absorption was avoided. Conversely, the effects of repaglinide on the pharmacokinetics of drugs with only a narrow margin between effective and toxic concentrations, such as digoxin or theophylline, were determined. The studies reported here compared monotherapy with combined therapies in healthy volunteers. There were no significant differences between the pharmacokinetic parameters of repaglinide when given as monotherapy and when administered concurrently with cimetidine. Similarly, the coadministration of repaglinide and digoxin did not influence the pharmacokinetics of digoxin administered alone. When repaglinide was coadministered with theophylline, the only pharmacokinetic change was that the peak plasma theophylline concentration was slightly reduced. No direct drug-drug interactions were found in these studies, suggesting that repaglinide may be coprescribed with cimetidine, digoxin, or theophylline at the dosage used for monotherapy.

Atorvastatin Coadministration May Increase Digoxin Concentrations by Inhibition of Intestinal P‐Glycoprotein‐Mediated Secretion

The effect of atorvastatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady‐state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady‐state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0.24) values, respectively Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P‐glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P‐glycoprotein transport, the influence of atorvastatin and its metabolites on P‐glycoprotein‐mediated digoxin transport in monolayers of the human colon carcinoma (Caco‐2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a Km of 110 μM. Atorvastatin (100 μM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P‐glycoprotein transport. Thus, the increase in steady‐state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.

Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice

To determine the contribution of the mdr1a gene product to digoxin pharmacokinetics, we constructed a physiologically based pharmacokinetic model for digoxin in mdr1a (−/−) and mdr1a (+/+) mice. After intravenous administration, total body clearance and tissue-to-plasma concentration ratios for muscle and heart were decreased in mdr1a (−/−) mice as compared with mdr1a (+/+) mice, and in particular, the digoxin concentration in the brain was 68-fold higher than that in mdr1a (+/+) mice at 12 h. On the other hand, mdr1a gene disruption did not change the contributions of renal and bile clearances to total clearance, the plasma protein binding, or the blood-to-plasma partition coefficient. Brain concentration–time profiles in mdr1a (+/+) and mdr1a (−/−) mice showed a different pattern from those in plasma and other tissues, indicating digoxin accumulation in the brain tissue. Because there was no difference in the uptake or release of digoxin by brain tissue slices from the two types of mice, we assumed the brain tissue compartment to consist of two parts (a well-stirred part with influx and efflux clearance and an accumulative part). Simulation with this model gave excellent agreement with observation when active efflux clearance across the blood+brain barrier was assumed to be zero in mdr1a (−/−) mice. The observations in other tissues in both types of mice were also well simulated.

Lack of Pharmacokinetic Interaction between Gemifloxacin and Digoxin in Healthy Elderly Volunteers

Gemifloxacin is a novel fluoroquinolone with a broad spectrum of antibacterial activity. The objective of this double-blind, randomized, placebo-controlled, 2-way crossover study was to demonstrate the lack of a pharmacokinetic interaction between gemifloxacin and digoxin. During two 14-day treatment periods, healthy elderly volunteers received digoxin (0.25 mg, once daily) co-administered on days 8–14 with either gemifloxacin (320 mg, p.o., once daily) or placebo. On day 14 of each period, blood samples and urine were collected for 24 h post dose and analysed for digoxin levels by radioimmunoassay. Steady-state digoxin pharmacokinetics were not affected by multiple dosing with gemifloxacin. There was no significant difference in digoxin values for the area under the plasma concentration-time curve over the dosing interval 0–24 h (AUC_(0–24)) or the trough plasma concentration (C24) after co-administration with either gemifloxacin or placebo. Geometric means for AUC_(0–24) and C24 were 18.1 and 17.8 ng·h/ml and 0.597 and 0.566 ng/ml, respectively. The point estimates (90% confidence intervals) for AUC_(0–24) and C24 (digoxin + gemifloxacin):(digoxin + placebo) were 1.01 (0.93, 1.10) and 1.05 (0.95, 1.16), respectively, entirely within the equivalence range (0.80, 1.25). There were no marked differences between co-administration regimens for maximum observed plasma concentration (C_max) or renal clearance values. Gemifloxacin was well tolerated during co-administration with digoxin, and the incidence of adverse events was similar to that seen with placebo. There were no clinically relevant changes in vital signs, electrocardiogram readings or laboratory parameters. In conclusion, this study demonstrates that gemifloxacin may be co-administered with digoxin without the need for digoxin dose adjustment.

Longitudinal assessment of a P-glycoprotein-mediated drug interaction of valspodar on digoxin.

Valspodar is a P-glycoprotein modulator currently under development as a multidrug resistance reversal agent in clinical oncology. A multiple-dose drug interaction study was performed to assess the influence of valspodar on digoxin, a substrate for P-glycoprotein. Twelve healthy volunteers received an oral digoxin loading dose of 1 mg on day 1, followed by 0.125 mg once daily to day 11. On day 7, a single oral 400-mg dose of valspodar was given, followed by a regimen of 200 mg twice daily from days 8 to 11. Serial blood samples and urine collections were obtained on days 6, 7, and 11 for digoxin pharmacokinetics and on days 7 and 11 for valspodar pharmacokinetics. On these days, blood pressure, pulse rate, and electrocardiograms were recorded at multiple time points. Coadministration of single-dose valspodar with steady-state digoxin on day 7 yielded an average 76% increase in digoxin AUC and a 62% decrease in digoxin renal clearance (both P = .0001). After a 5-day coadministration period, digoxin AUC increased by an average 211% and apparent total body clearance was decreased by 67% (day 11) compared with steady-state administration of digoxin alone (day 6). Contributing to the change in total body clearance were decreases in both renal clearance (73%) and apparent nonrenal clearance (58%). Both drugs were well tolerated throughout the study. There was no clinically relevant change in the effect of digoxin on vital signs or electrocardiographic parameters when administered with single- or multiple-dose valspodar compared with administration alone in volunteers with healthy cardiovascular systems. Coadministration of oral valspodar and oral digoxin resulted in a twofold to threefold increase in digoxin systemic exposure. On the basis of these data in healthy volunteers, an initial digoxin dose reduction of 50% would appear to be appropriate when beginning oral valspodar treatment. Throughout the period of coadministration, patients should be carefully monitored for clinical signs of digoxin toxicity in conjunction with digoxin therapeutic drug monitoring. Together, these should serve as the basis for individualized digoxin dose titration.

The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin.

Recent data point to the contribution of P-glycoprotein (P-gp) to digoxin elimination. On the basis of clinical observations of patients in whom digoxin levels decreased considerably when treated with rifampin, we hypothesized that concomitant rifampin therapy may affect digoxin disposition in humans by induction of P-gp. We compared single-dose (1 mg oral and 1 mg intravenous) pharmacokinetics of digoxin before and after coadministration of rifampin (600 mg/d for 10 days) in 8 healthy volunteers. Duodenal biopsies were obtained from each volunteer before and after administration of rifampin. The area under the plasma concentration time curve (AUC) of oral digoxin was significantly lower during rifampin treatment; the effect was less pronounced after intravenous administration of digoxin. Renal clearance and half-life of digoxin were not altered by rifampin. Rifampin treatment increased intestinal P-gp content 3.5 +/- 2.1-fold, which correlated with the AUC after oral digoxin but not after intravenous digoxin. P-gp is a determinant of the disposition of digoxin. Concomitant administration of rifampin reduced digoxin plasma concentrations substantially after oral administration but to a lesser extent after intravenous administration. The rifampin-digoxin interaction appears to occur largely at the level of the intestine. Therefore, induction of intestinal P-gp could explain this new type of drug-drug interaction.

Population analysis for the optimization of digoxin treatment in Japanese paediatric patients.

Information about the pharmacokinetics of digoxin in paediatric patients is limited. We therefore aimed to investigate the effects of physiological factors on the digoxin clearance in Japanese paediatric patients. We used routinely collected therapeutic drug monitoring data (n=544), derived from the steady-state serum concentrations of digoxin in 181 hospitalized paediatric patients. Of those physiological factors which have been examined in this study, age and total body weight were most closely correlated with digoxin clearance. Data on neonates within the first postnatal month indicated a tendency towards lower clearance for premature neonates than full-term neonates (P<0.01). Digoxin clearance was reduced by spironolactone in patients younger than 4 months (P<0.05). Patients with congestive heart failure showed a lower digoxin clearance than the others (P<0.001). Serum creatinine and gender did not have a statistically significant effect on digoxin clearance. Age and total body weight are important factors influencing digoxin clearance in children. Spironolactone affected digoxin clearance and needs to be considered when dosing paediatric subjects.

Effect of itraconazole on the pharmacokinetics of digoxin in guinea pigs.

The effect of itraconazole (ITZ) on the pharmacokinetics of digoxin (DGX) was investigated in guinea pigs. The plasma concentrations of DGX in guinea pigs following treatment with ITZ (20 mg/kg intraperitoneally (i.p.)) after intravenous (i.v.) administration of DGX (0.125 mg/kg) were significantly higher than in the controls. The percentage cumulative excretion (6.9%) of DGX in bile of the ITZ-treated group up to 6 h after administration of DGX was significantly reduced (p < 0.05) compared with 10.5% in the control. The percentage cumulative excretion (3.1%) of DGX in urine of the ITZ-treated group up to 6 h after administration was also one third that in the controls. The total, biliary, renal and metabolic clearances for DGX in the ITZ-treated group were significantly reduced, while the V(dss) was unaffected. The plasma unbound fraction of DGX (ranged 47-58%) in the ITZ-treated group was generally similar to that in the controls (50-57%). The blood-to-plasma concentration ratio of DGX (range 1.28-1.42) in the absence of ITZ did not change in the presence of ITZ. Based on these results, the pharmacokinetic interaction between DGX and ITZ may be due not only to a reduction in the renal clearance but also to a reduction in the metabolic clearance of DGX by ITZ.

A review of eprosartan pharmacokinetic and pharmacodynamic drug interaction studies.

A series of clinical pharmacology studies was conducted to characterize potential interactions between eprosartan and other commonly prescribed drugs. Separate studies assessed the effect of eprosartan on the pharmacokinetics of digoxin and hydrochlorothiazide (HCTZ) and the pharmacodynamics of warfarin and glyburide (glibenclamide), as well as the effects of ranitidine, HCTZ, fluconazole, and ketoconazole on eprosartan pharmacokinetics. Eprosartan had no significant effect on the pharmacokinetics of digoxin and HCTZ and the pharmacodynamics of warfarin and glyburide. Thus, no dosing adjustments are necessary during concomitant therapy with these agents. Ranitidine, HCTZ, ketoconazole, and fluconazole had no effect on eprosartan pharmacokinetics. Single or multiple oral doses of eprosartan were safe and well tolerated when coadministered with these agents.

Improved sensitivity of digoxin assay by modification of the EMIT 2000 method.

A modified EMIT 2000 digoxin assay was developed on the Cobas Mira plus analyzer for the determination of very low plasma concentrations of the drug. The major modifications were a higher plasma volume withdrawn during the analysis step and calibration curves constructed in the range 0-2 ng/ml using calibrators made up with biological matrix. Assays were controlled with an internal, four-level quality control (targets: 0.15; 0.60; 1.70; 2.70 ng/mL). The within-day and day-to-day mean observed values +/- SD (n = 10) of these quality controls were 0.14 +/- 0.02 and 0.15 +/- 0.02 ng/mL; 0.57 +/- 0.01 and 0.64 +/- 0.03 ng/mL; 1.55 +/- 0.06 and 1.62 +/- 0.04 ng/mL, 2.82 +/- 0.09 and 2.82 +/- 0.12 ng/mL, respectively. The detection and the quantification limits were 0.02 and 0.08 ng/mL, respectively. No significant difference was observed between digoxin plasma concentrations measured by the original and the modified EMIT 2000 digoxin assay in 25 plasma specimens, ranging from 0.4 to 3.0 ng/mL, from patients receiving the drug. This modified digoxin EMIT 2000 assay was subsequently used to study digoxin pharmacokinetics after each of 18 healthy volunteers was administered a single 0.5 mg oral dose. The pharmacokinetic parameters found in this study were in accordance with the literature in healthy subjects, using radioimmunoassay (RIA) for digoxin plasma concentration determinations. In conclusion, the lower limit of quantification of this modified EMIT 2000 digoxin assay is similar to that of RIA and can serve as a valuable screen for digoxin pharmacokinetic interactions studies.

Pharmacokinetic interaction of sparfloxacin and digoxin

Sparfloxacin, a broad-spectrum, oral fluoroquinolone antimicrobial agent, has a long elimination half-life that permits once-daily administration. Antibiotics may increase the oral bioavailability of digoxin, leading to increases in its plasma concentration. Since patients treated with sparfloxacin may be receiving concurrent treatment with digoxin, the possibility of an interaction between sparfloxacin and digoxin was examined in a doublemasked, placebo-controlled, multipledose, two-way crossover study in 24 healthy male volunteers between 20 and 49 years of age. All subjects were given digoxin 0.3 mg once daily throughout the 20-day study. Sparfloxacin (or placebo) was given as a 400-mg loading dose on day 1, followed by single 200-mg daily doses for 9 days, with crossover to the alternate treatment on days 11 through 20. Plasma levels of digoxin were analyzed by validated radioimmunoassay, and plasma levels of sparfloxacin were analyzed by validated high-performance liquid chromatography. Concomitant administration of sparfloxacin and digoxin was generally well tolerated. Mean values for steady-state area under the concentration-time curve over 24 hours for the 2 treatments were virtually identical: 28.4 ng/h per mL −1 for digoxin administered with placebo and 28.9 ng/h per mL −1 for digoxin administered concomitantly with sparfloxacin. Mean steady-state maximum plasma concentrations were 3.91 and 3.59 ng/mL for digoxin with placebo and digoxin with sparfloxacin, respectively. Mean steady-state trough plasma digoxin concentrations for the 2 treatments were 0.87 and 0.89 ng/mL, respectively. Mean times to steady-state maximum plasma concentrations were identical at 0.89 hours for both treatments. Mean steady-state oral clearance was 10.6 L/h for digoxin alone and 10.4 L/h for digoxin with sparfloxacin. Thus administration of sparfloxacin in combination with digoxin did not alter the pharmacokinetics of digoxin in healthy male volunteers aged 20 to 49 years. Steady-state plasma sparfloxacin concentrations were consistent with those obtained in other multiple-dose phase I studies, suggesting that digoxin does not alter the steady-state pharmacokinetics of sparfloxacin.

Clinical pharmacokinetics of troglitazone.

Troglitazone is a new thiazolidinedione oral antidiabetic agent approved for use to improve glycaemic control in patients with type 2 diabetes. It is rapidly absorbed with an absolute bioavailability of between 40 and 50%. Food increases the absorption by 30 to 80%. The pharmacokinetics of troglitazone are linear over the clinical dosage range of 200 to 600 mg once daily. The mean elimination half-life ranges from 7.6 to 24 hours, which facilitates a once daily administration regimen. The pharmacokinetics of troglitazone are similar between patients with type 2 diabetes and healthy individuals. In humans, troglitazone undergoes metabolism by sulfation, glucuronidation and oxidation to form a sulfate conjugate (M1), glucuronide conjugate (M2) and quinone metabolite (M3), respectively. M1 and M3 are the major metabolites in plasma, and M2 is a minor metabolite. Age, gender, type 2 diabetes, renal impairment, smoking and race do not appear to influence the pharmacokinetics of troglitazone and its 2 major metabolites. In patients with hepatic impairment the plasma concentrations of troglitazone, M1 and M3 increase by 30%, 4-fold, and 2-fold, respectively. Cholestyramine decreases the absorption of troglitazone by 70%. Troglitazone may enhance the activities of cytochrome P450 (CYP) 3A and/or transporter(s) thereby reducing the plasma concentrations of terfenadine, cyclosporin, atorvastatin and fexofenadine. It also reduces the plasma concentrations of the oral contraceptive hormones ethinylestradiol, norethindrone and levonorgestrel. Troglitazone does not alter the pharmacokinetics of digoxin, glibenclamide (glyburide) or paracetamol (acetaminophen). There is no pharmacodynamic interaction between troglitazone and warfarin or alcohol (ethanol). Pharmacodynamic modelling showed that improvement in fasting glucose and triglyceride levels increased with dose from 200 to 600 mg. Knowledge of systemic troglitazone exposure within a dose group does not improve the prediction of glucose lowering response or adverse effects beyond those based on the administered dose.

Effect of Troglitazone on Urinary Excretion of 6β‐Hydroxycortisol

Coadministration of troglitazone reduces the plasma concentrations of terfenadine and ethinyl estradiol, Because these drugs are metabolized at least in part by cytochrome P450 3A (CYP3A), it is possible that troglitazone induces CYP3A activity, thereby reducing plasma concentrations of these agents. Known inducers of CYP3A, such as rifampin, phenytoin, carbamazepine, and phenobarbital, increase the urinary excretion of 6β‐hydroxycortisol and the ratio of 6β‐hydroxycortisol to cortisol. This evaluation examined the effect of troglitazone on urinary excretion of 6β‐hydroxycortisol and the ratio of 6β‐hydroxycortisol to cortisol as a marker for CYP3A induction. Urine samples were collected from 11 subjects who completed a study evaluating the effect of multiple‐dose administration of troglitazone 400 mg once daily (days 11‐20) on the steadystate pharmacokinetics of digoxin (0.25 mg daily on days 1‐20). A single urine sample was collected at baseline on day 1, and 24‐hour urine samples were collected on days 10 and 20. Mean ± standard deviation 24‐hour excretion rate of cortisol was unchanged, whereas that of 6β‐hydroxycortisol increased during troglitazone administration. The ratio of 24‐hour urinary 6β‐hydroxy‐cortisol to cortisol excretion increased from 7.4 ± 2.7 on day 10 to 16.1 ± 6.2 on day 20. The ratio observed on day 10 was similar to that obtained at baseline. These results are consistent with the hypothesis that troglitazone induces CYP3A activity.

Concomitant troglitazone does not change the steady-state pharmacokinetics of digoxin,

Concomitant troglitazone does not change the steady-state pharmacokinetics of digoxin,

Effect of troglitazone on steady-state pharmacokinetics of digoxin.

Twelve healthy subjects participated in a study to determine the effect of multiple doses of troglitazone on the steady-state pharmacokinetics of digoxin. Subjects received digoxin 0.25 mg orally once daily on days 1 through 20 and 400 mg of troglitazone orally once daily on days 11 through 20. Serial plasma samples and 24-hour urine samples collected before and after the doses on days 10 and 20 were analyzed for digoxin using a radioimmunoassay method. Eleven subjects completed the study. Administration of multiple oral doses of digoxin and troglitazone was well tolerated. Mean values for maximum concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from 0 to 24 hours (AUC0-24) of digoxin on day 10 were similar to those on day 20. Mean day 10 digoxin values for minimum concentration (Cmin), apparent oral clearance (Cl/F), total urinary excretion from 0 to 24 hours (Ae0-24), and renal clearance (Clr) were also similar to corresponding values on day 20. Thus, concomitant administration of multiple-dose troglitazone does not alter the steady-state pharmacokinetics of digoxin.

Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833.

Mice lacking mdr1-type P-glycoproteins (mdr1a/1b [-/-] mice) display large changes in the pharmacokinetics of digoxin and other drugs. Using the kinetics of digoxin in mdr1a/1b (-/-) mice as a model representing a complete block of P-glycoprotein activity, we investigated the activity and specificity of the reversal agent SDZ PSC833 in inhibiting mdr1-type P-glycoproteins in vivo. Oral PSC833 was coadministered with intravenous [3H]digoxin to wild-type and mdr1a/1b (-/-) mice. The direct excretion of [3H]digoxin mediated by P-glycoprotein in the intestinal mucosa of wild-type mice was abolished by administration of PSC833. Hepatobiliary excretion of [3H]digoxin was markedly decreased in both wild-type and mdr1a/1b (-/-) mice by PSC833, the latter effect indicating that in vivo, PSC833 inhibits not only mdr1-type P-glycoproteins, but also other drug transporters. Upon coadministration of PSC833, brain levels of [3H]digoxin in wild-type mice showed a large increase, approaching (but not equaling) the levels found in brains of PSC833-treated mdr1a/1b (-/-) mice. Thus, orally administered PSC833 can inhibit blood-brain barrier P-glycoprotein extensively, and intestinal P-glycoprotein completely. These profound pharmacokinetic effects of PSC833 treatment imply potential risks, but also promising pharmacological applications of the use of effective reversal agents.