Changes In Pharmacokinetics Of Digoxin Research Articles

THE DANGER OF DIGOXIN: TOXICITY WITHIN THE "THERAPEUTIC” RANGE

THE DANGER OF DIGOXIN: TOXICITY WITHIN THE "THERAPEUTIC” RANGE

Changes in digoxin pharmacokinetics associated with hepatic P-glycoprotein upregulation in rats with non-alcoholic fatty liver disease.

Upregulation of hepatic P-glycoprotein (P-gp) expression has been reported in patients with non-alcoholic fatty liver disease (NAFLD) and rodent models thereof. Here, we explored the changes hepatic P-gp expression and activity in a NAFLD rat model and the effects thereof on the pharmacokinetics of digoxin (a probe substrate of P-gp). Rats were fed a 1% (w/w) orotic acid-containing diet for 20days to induce NAFLD; control rats received a normal diet. P-gp expression and biliary digoxin excretion were examined. The pharmacokinetics of digoxin were evaluated after it had been administered intravenously (10μg·kg-1 ) and orally (200μg·kg-1 ) to control and NAFLD rats. The total areas under the plasma concentration-time curves (AUCs) of digoxin after intravenous and oral administration were significantly smaller (by 39.1% and 73.0%, respectively) in NAFLD rats because of faster biliary digoxin excretion, reflecting elevations of hepatic P-gp expression and activity. Notably, the steady-state volume of distribution rose by 98.2%, while extent of oral bioavailability fell by 55.5% in NAFLD rats. This is the first study to report digoxin pharmacokinetic changes caused by hepatic P-gp upregulation in NAFLD. Further studies are needed to explore the clinical impact of enhanced P-gp-mediated biliary excretion on pharmacotherapies using P-gp substrates in patients with NAFLD.

No clinically significant drug interactions between lenalidomide and P-glycoprotein substrates and inhibitors: results from controlled phase I studies in healthy volunteers

PurposeLenalidomide, a weak substrate of P-glycoprotein (P-gp) in vitro, is an oral anticancer drug eliminated predominantly via renal excretion as unchanged compound. The role of P-gp in lenalidomide disposition and the associated clinical relevance were evaluated.MethodsTwo phase I, crossover studies were conducted in healthy volunteers. In Study 1, subjects received lenalidomide (10 mg × 7 days) alone or with the P-gp substrate digoxin (0.5 mg on Day 5). In Study 2, subjects received lenalidomide (a single 25 mg dose) alone, the P-gp inhibitor quinidine (300–600 mg twice-daily × 5 days) plus lenalidomide (on Day 4), the P-gp inhibitor/substrate temsirolimus (a single 25 mg dose) alone, or lenalidomide plus temsirolimus. Pharmacokinetic and safety data were collected for lenalidomide and the co-administrated drugs.ResultsThere were no significant changes in the maximum concentration (C max) and area under the plasma concentration–time curve (AUC) of lenalidomide when co-administered with quinidine, digoxin, or temsirolimus. Neither the rate nor the capacity of lenalidomide renal excretion was affected by quinidine or temsirolimus, in addition lenalidomide absorption rate and bioavailability remained unchanged. Furthermore, lenalidomide had no significant effect on blood C max and AUC of temsirolimus and its active metabolite sirolimus (also a P-gp inhibitor/substrate). The C max of digoxin was slightly higher (+14 %) when administered with lenalidomide versus placebo. There were no other changes in digoxin pharmacokinetics upon co-administration with lenalidomide. No remarkable safety findings were observed.ConclusionsThere are no clinically significant pharmacokinetic interactions between lenalidomide and substrates or inhibitors of P-gp.

Changes in Digoxin Pharmacokinetics Treated with Lipopolysaccharide in Wistar Rats

Lipopolysaccharide (LPS) is a highly bioactive substance that can cause local as well as systemic damage to various organs of both humans and animals, even at very low doses. However, there are a few reports on drug pharmacokinetics during endotoxemia. In this study, we analyzed the pharmacokinetics of digoxin (a therapeutic agent for cardiac insufficiency) as a probe drug for a two-compartment model in a rat model of endotoxemia induced by LPS for 5 d. Digoxin was given to Wistar rats intravenously (i.v.), orally (p.o.), and intra-intestinally using an in situ closed-loop method (loop). The AUCi.v. was significantly increased in the LPS (+) group throughout the experiment (p<0.05). There was significant decrease in V2 (volume of distribution of tissue compartment) on Day 1-3 (p<0.05). On Day 1-2 after LPS administration, the AUCp.o. was significantly increased in the LPS (+) group (p<0.05). The AUCloop was significantly increased throughout the experiment (p<0.05). The elimination rate constant was unchanged. Thus LPS administration affected the absorption but not the excretion of digoxin. The findings of this study suggest that digoxin absorption increased and the volume of distribution of tissue compartment decreased after LPS administration (5 mg/kg, i.p.). It appears that digoxin pharmacokinetics recover over 3 d after LPS administration.

Effects of CpG-DNA from Escherichia coli on Digoxin Pharmacokinetics

Deoxyribonucleic acid (DNA) from bacteria or viruses has been reported as one of the pathogen-associated molecular patterns (PAMPs) and a substance that can induce endotoxemia-like inflammation in animals. However, there has been no report on digoxin pharmacokinetics in the inflammation induced by bacterial DNA containing unmethylated CpG motifs (CpG-DNA). In this study, we investigated the effects of CpG-DNA on digoxin pharmacokinetics. We determined the degree of lipopolysaccharide contamination in CpG-DNA solution and examined the changes in digoxin pharmacokinetics in rats after CpG-DNA administration. In addition, plasma concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and nitrite/nitrate (NOx) were determined after CpG-DNA administration (5 mg/kg, i.p.). The AUC0-24 of digoxin increased significantly on Day 1-3 and CL/F decreased on Day 1 and Day 2 after CpG-DNA administration. On Day 7 after CpG-DNA administration, there were no significant differences in AUC0-24 and CL/F compared with the control group (without CpG-DNA administration). However, Kel remained relatively unchanged throughout the experiment. Plasma TNF-alpha concentrations were significantly increased at 1 h and plasma IL-1beta concentrations were significantly decreased at 6 h after administration of CpG-DNA, while plasma NOx concentrations were significantly increased at 12 h after CpG-DNA administration, compared with the control group. These findings suggest that CpG-DNA (5 mg/kg) induces a transient inflammatory condition, and that AUC0-24 and CL/F of digoxin were altered after CpG-DNA administration. Digoxin pharmacokinetics recovered within 7 d after CpG-DNA exposure.

Vitamin E formulation affects digoxin absorption by inhibiting P-glycoprotein (P-GP) in humans

Water-soluble vitamin E(D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) may increase oral drug absorption. In vitro and animal data suggest that TPGS inhibits P-gp. It is unknown whether α-tocopherol acetate(TA), the more common formulation of vitamin E, has similar drug interaction potential. This study aimed to determine whether TPGS and TA cause comparable P-gp inhibition in humans. Ten healthy subjects received digoxin 0.5mg POx1 to determine baseline digoxin pharmacokinetics (PK). They then received TA and TPGS (400 IU PO Q12H x15d) in random order with a 4-week washout between treatments. Digoxin 0.5mg PO was given on days 1 and 15. Serum digoxin concentrations were measured at t=0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours; 12-lead EKG was monitored at t=0, 3 and 6 hours after each digoxin dose. Genotyping for MDR1(exon 26, C3435T) was determined for variant alleles. Digoxin PK were not different between 3435CC homozygous and 3435CT allele carriers. Digoxin PK from each treatment were: (See Table) In summary, TPGS but not TA, altered PK without affecting pharmacodynamics of digoxin. Changes in digoxin PK with TPGS were not affected by 3435CT mutation in MDR1 gene. Clinical Pharmacology & Therapeutics (2004) 75, P95–P95; doi: 10.1016/j.clpt.2003.11.364 Table 1. p<0.05 compared with baseline; no EKG changes were observed. (Data are mean±SD). Cmax[ng/mL] AUC0–24[ng·h/mL] 3.7±3.0

Effect of grapefruit juice on digoxin pharmacokinetics in humans

Grapefruit juice is responsible for drug interactions mediated by intestinal cytochrome P4503A4 inhibition and possibly P-glycoprotein inhibition in enterocytes. Our main objective was to determine whether grapefruit juice alters the bioavailability of digoxin, a P-glycoprotein substrate. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by P-glycoprotein genetic polymorphism. Twelve healthy volunteers participated in this open randomized crossover study comparing the effect of grapefruit juice consumption (versus water) on the pharmacokinetics of a single oral dose of digoxin (0.5 mg). The P-glycoprotein genotype was determined according to MDR1 genetic polymorphism in exon 26 (C3435T). Grapefruit juice had no significant effect on the maximum plasma drug concentration (C(max)) of digoxin or the area under the plasma concentration-time curve (AUC) from time zero to 48 hours. However, there was a 9% increase in the digoxin AUC from time zero to 4 hours and from time zero to 24 hours (P =.01) during grapefruit juice administration. The digoxin renal clearance remained unchanged during both periods. No relationship between MDR1 C3435T genotype and early digoxin pharmacokinetic changes could be detected. The modest changes in digoxin pharmacokinetics observed during grapefruit juice ingestion do not support an important P-glycoprotein inhibition. Under our experimental conditions, grapefruit juice-mediated P-glycoprotein inhibition does not appear to play a relevant role in drug interactions, at least when assessed by use of digoxin disposition kinetics.

Pharmacokinetic evaluation of the digoxin-amiodarone interaction

Amiodarone is known to raise serum digoxin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction in 10 normal subjects. The pharmacokinetic variables for digoxin were determined after a 1.0 mg intravenous dose of digoxin in each subject, before and after oral amiodarone, 400 mg daily for 3 weeks. During amiodarone administration, systemic clearance of digoxin was reduced from 234 +/- 72 ml/min (mean +/- standard deviation) to 172 +/- 33 ml/min (p less than 0.01). This was due to reductions in both renal clearance (from 105 +/- 39 to 84 +/- 15 ml/min) (p less than 0.05) and nonrenal clearance (from 130 +/- 38 to 88 +/- 20 ml/min) (p less than 0.01). Digoxin half-life of elimination was prolonged from 34 +/- 13 to 40 +/- 16 hours (p less than 0.05). Digoxin volume of distribution was not significantly changed. Amiodarone caused a three- to fivefold increase in serum reverse triiodothyronine levels, but changes in thyroid function were not quantitatively related to the changes in digoxin pharmacokinetics. These alterations in digoxin pharmacokinetics produced by amiodarone explain the increase in serum digoxin level that has been observed when this drug combination has been used clinically.

Clinical pharmacokinetics of cardiac glycosides in patients with renal dysfunction.

Clinical pharmacokinetics of cardiac glycosides in patients with renal dysfunction.