Bioavailability Of Digoxin Research Articles

Novel Indole Derivative as the First P-glycoprotein Inhibitor from the Skin of Indian Toad (Bufo melanostictus)

To study the inhibitory effect of novel indole derivative (NID) from Indian toad skin (Bufo melanostictus) on permeability glycoprotein (P-gp). Dried Indian toad skin was used to isolate NID with column chromatography, and its structure was elucidated by infrared spectra, 13C nuclear magnetic resonance (NMR), 1H NMR spectra, and liquid chromatography-mass spectrometry. Female Wistar rats were used to determine LD50, in vitro permeability studies were done with the intestinal sac method, and in vivo pharmacokinetic studies were carried out to prove the P-gp inhibition using the rat model. The NID has shown increased clear permeability Papp (x10-6 cm/sec) significantly (p<0.001) from 1.04±0.11 to 2.90±0.08 in ileum 1.44±0.14 to 3.92±0.13 in jejunum this in vitro results confirmed that P-gp inhibited, this was further confirmed by in vivo studies in in vivo studies observed increased oral bioavailability of digoxin (DIG) significantly in NID treated groups from 3.26±0.25 to 7.47±0.18 ng/mL, the volume of distribution decreased from 232.56±64.59 to 86.57±7.04 L/kg. Area under the curve increased from 37.89±1.13 to 64.62±0.70 ng/mL/hr. This demonstrates NID increased the oral bioavailability of DIG significantly. Many compounds were isolated from the Indian toad skin. This NID was not reported earlier. Results demonstrate NID increased the oral bioavailability of DIG significantly. The isolated NID from Indian toad skin proved as a potent P-gp inhibitor in both in vitro and in vivo studies, and further studies are needed to develop as a possible new drug candidate.

Digoxin absorption decreased independently of P-gp activity in rats with irinotecan-induced gastrointestinal damage

BackgroundIrinotecan (CPT-11) is clinically known to cause severe diarrhea and gastrointestinal damage. Recently, we have reported that CPT-11-induced gastrointestinal damage is associated with the upregulation of intestinal P-glycoprotein (P-gp) expression and decreased absorption of its substrate, dabigatran etexilate (DABE), using a rat model. However, the P-gp activity or its contribution to the decreased absorption remains unclear. The aim of this study was to quantitatively evaluate how P-gp activity changes in rats with CPT-11-induced gastrointestinal damage, as assessed by the absorption of digoxin (DGX), a typical P-gp substrate.MethodsMale Sprague-Dawley rats were intravenously administered CPT-11 at a dose of 60 mg/kg/day for 4 days to induce gastrointestinal damage. Then, the rats were administered DGX orally (40 μg/kg), after some of them were orally administered clarithromycin (CAM; 10 mg/kg), a P-gp inhibitor. DGX (30 μg/kg) was administered intravenously to determine the bioavailability (BA). The rats’ DGX plasma concentration profiles were determined using LC-MS/MS.ResultsCPT-11 treatment decreased the maximum concentration (Cmax) and area under the plasma concentration-time curve (AUCpo) of DGX, which does not contradict to the DABE study. Although in the CPT-11-treated group the BA of DGX was significantly decreased to 40% of the control value, CAM did not affect the BA of DGX in the CPT-11-treated group.ConclusionsIncreased P-gp expression in rats with CPT-11-induced gastrointestinal damage is not necessarily associated with increased P-gp activity or contribution to the drug absorption in vivo. The decreased DGX absorption observed in this study might be attributable to other factors, such as a reduction in the absorptive surface area of the gastrointestinal tract.

Effect of purple grape juice on the pharmacokinetics of digoxin: Results of a food-drug interaction study

Digoxin is a glycosidic, cardiotonic plant extract with a narrow therapeutic window. The purpose of the study was to investigate the effects of purple grape juice on the pharmacokinetics of digoxin in rats. A randomized, controlled, single- and multiple-dose study was conducted to evaluate the pharmacokinetic profiles of orally and intravenously administered digoxin. The plasma concentration of digoxin was determined by radioimmunoassay using a gamma counter, and a Caco-2 cell transport model was used to investigate the potential mechanism by which purple grape juice affects the pharmacokinetics of digoxin. The results show that multiple-dose purple grape juice caused a remarkable increase in the AUC, Cmax, and Ka of orally administered digoxin (p < 0.05); only a single dose increased the digoxin AUC0-∞ by 72.80% (p < 0.05). Other parameters were not significantly affected. The study of intravenously administered digoxin found no significant difference in the pharmacokinetic characteristics of the two dosing groups (p > 0.05). The Caco-2 transwell experiments indicated that both the pure purple grape juice and its ethyl acetate extract significantly inhibited digoxin basolateral-to-apical (B→A) transport at concentrations of 10%, 30%, and 50% with dose dependency. These results confirmed that the improvement in bioavailability of digoxin resulted from the inhibition of P-gp by purple grape juice at the level of the gastrointestinal wall. Purple grape juice can increase the bioavailability of orally administered digoxin, especially with multiple doses. This information suggests that co-administration of oral digoxin and purple grape juice may require a dose adjustment. .

Polysorbate 20 increases oral absorption of digoxin in wild-type Sprague Dawley rats, but not in mdr1a(-/-) Sprague Dawley rats

The aim was to investigate the ability of polysorbate 20 to alter oral digoxin absorption in vitro and drug exposure in vivo via modulation of transporter mediated efflux. Transport studies were performed in MDCKII-MDR1 and Caco-2 cells using 3H-digoxin. Pharmacokinetic studies were performed in wild type and mdr1a deficient Sprague Dawley rats. 3H-digoxin was quantified using liquid scintillation counting. The results showed an increased absorptive transport and a reduced secretory transport in MDCKII-MDR and Caco-2 cells as a function of polysorbate 20 concentrations. The secretory transport (B–A) of digoxin was reduced by 50% at lower polysorbate 20 concentrations than required to increase the absorptive transport (A-B). In vivo, the oral bioavailability of digoxin in wild type animal was increased by 10–25% (w/v) polysorbate 20. In mdr1a deficient Sprague Dawley rats 25% (w/v) polysorbate 20 did not alter the absorption of digoxin after oral administration, but digoxin exposure was significantly different between wild type and mdr1a deficient rats. In conclusion, polysorbate 20 increased absorptive transport across Caco-2 cell monolayers and in vivo in rats in a concentration dependent manner, most likely via inhibition of P-gp rather than through solubilization of digoxin.

ABCB1 gene variants, digoxin and risk of sudden cardiac death in a general population

ObjectiveThe ATP-binding cassette B1 (ABCB1) gene encodes P-glycoprotein, a transport protein, which plays an important role in the bioavailability of digoxin. We aimed to investigate the interaction between variants within...

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APhA honors outstanding achievements at Annual Meeting

Each year, APhA recognizes exceptional contributors to the profession at the Annual Meeting. The following award winners will be honored at APhA2014 in Orlando.

Intestinal microbiome and digoxin inactivation: meal plan for digoxin users?

There is an increasing interest in the role of intestinal microbiome in human diseases and therapeutic agents' bioavailability, activity and toxicity. Epidemiological data show that the bioavailability of digoxin, a widely used agent for heart disease, varies among individuals. The inactivation of digoxin was found when it was incubated with gut bacterium Eggerthella lenta in vitro decades ago. However, the underlying mechanisms of digoxin inactivation are still unclear. A recent study using animal models uncovered this mystery, which suggested that arginine supplements might be a potential intervention in increasing digoxin activity by inhibiting the expression of cardiac glycoside reductase gene operons that inactivated digoxin. This perspective summarizes the connections among the intestinal microbiome, the digoxin inactivation, the metabolism of arginine. We also discuss several issues yet to be addressed in the future, making better strategies in the application of dietary arginine supplements for digoxin users.

Influence of capsaicin on fluctuation of digoxin pharmacokinetics in lipopolysaccharide-treated rats

In the present study, we investigated the influence of Cap on digoxin pharmacokinetics in lipopolysaccharide (LPS)-treated rats.After the oral administration of digoxin (0.1 mg/kg), the area under the plasma concentration-time curve (AUC) of digoxin increased significantly until day 3 after LPS treatment. In the LPS + Cap group, the recovery period of AUC was shortened to 3 days. On days 5 and 7, the maximum plasma concentrations decreased significantly as compared to the control group. The bioavailability of digoxin in LPS group was higher than that in the LPS + Cap group.The hepatic cytochrome P450 (CYP) 3A2 content decreased significantly until day 5 after LPS administration, but it returned to the control level until 5 days in the LPS + Cap group. Hepatic CYP3A2 mRNA expression of LPS group decreased significantly until day 3, but it returned to the control level on day 3 and increased significantly until day 7 in the LPS + Cap group.The DNA-binding activity of pregnane X receptor (PXR) was increased on days 3–7 in the Cap and LPS + Cap group.Cap decreased the absorption of digoxin by inducing CYP3A2 mRNA expression via indirect activation of PXR in LPS-treated rats.

Effect of berberine on the pharmacokinetics of substrates of CYP3A and P‐gp

The in vivo effects of berberine (BBR), the widely used bioactive herbal ingredient from many traditional Chinese medicinal herbs, on the pharmacokinetics of carbamazepine (CBZ, a substrate of CYP3A) and its metabolite carbamazepine 10,11-epoxide (ECBZ), digoxin (DIG, a substrate of P-gp) and cyclosporine A (CsA, a dual substrate of CYP3A and P-gp) were evaluated in rats. After a 2-week pretreatment with BBR, the pharmacokinetic parameters of i.g. administered CBZ and ECBZ were not significantly altered. The pharmacokinetics of i.v. administered DIG was not modified by single and 2-week pretreatments with BBR, but a dose-dependent increase in AUC and C(max) was observed in the i.g. administered DIG parameters in rats. The AUCs of DIG with BBR (30 mg/kg, 100 mg/kg) were 133%, 170% (single) and 123%, 169% (2-week) of control, respectively. The AUC and C(max) of i.g. administered CsA with a 2-week pretreatment with BBR increased by 62% and 43% (BBR 30 mg/kg, p < 0.05), 96% and 60% (BBR 100 mg/kg, p < 0.01), compared with the control. In conclusion, berberine produced a dose-dependent increased bioavailability of digoxin and cyclosporine A by inhibition of intestinal P-gp. No significant changes in CYP3A activity by berberine were observed.

PRECLINICAL STUDY: Disposition of Δ9 tetrahydrocannabinol in CF1 mice deficient in mdr1a P‐glycoprotein

P-glycoprotein (P-gp) plays a major role in drug efflux. All the transported substrates are more or less hydrophobic and amphiphatic in nature. Being lipophilic, Delta(9) tetrahydrocannabinol (THC), the main cannabis component, could be a potential P-gp substrate. The aim of this project was to determine the contribution of the mdr1a gene product to THC disposition. Therefore, oral THC and digoxin (substrate test for P-gp) pharmacokinetics have been investigated in the intestinal epithelium and in the brain capillary endothelium of CF1 mdr1a-/- mice (mice naturally deficient in P-gp). These pharmacokinetics were compared to THC and digoxin oral pharmacokinetics in wild type mice mdr1a+/+ (not P-gp deficient). The application of Bailer's method showed that THC total exposure measured by the area under the plasma concentration time curve was 2.17-fold higher in CF1 mice naturally deficient in P-gp than in wild type mice after oral administration of 25 mg/kg of THC, and 2.4-fold higher after oral administration of 33 microg/kg of digoxin. As a consequence, the oral bioavailability of THC and digoxin was higher in naturally P-gp-deficient mice. We concluded that P-gp limits THC oral uptake and mediates direct drug excretion from the systemic circulation into the intestinal lumen.

Lack of a pharmacokinetic interaction between a new smoking cessation therapy, varenicline, and digoxin in adult smokers

This study investigated the effect of varenicline on the multiple-dose pharmacokinetics of digoxin. Eighteen smokers were randomized to receive digoxin (Lanoxicaps 0.2 mg QD) with varenicline 1 mg BID or placebo for 14 days. Varenicline had no clinically relevant effect on the digoxin steady-state exposure, as evidenced by the 90% confidence intervals for the ratios of AUC(0-24) (87.5-108%) and C(min) (83.8-116%) wholly contained within 80-125%. Digoxin C(max) and T(max) remained unchanged in the presence of varenicline, consistent with no apparent alteration in digoxin bioavailability. A minimal 11.3% increase in digoxin renal clearance was noted during varenicline treatment while having no impact on its systemic exposure. Results are supported by mechanistic evidence in Caco-2 cell monolayers that varenicline is neither a P-gp substrate nor an inhibitor of P-gp-mediated efflux of digoxin. Co-administration of varenicline and digoxin was well tolerated. The results suggest that digoxin can be safely administered with varenicline without the need for dose adjustment.

Altered Oral Bioavailability and Pharmacokinetics of P-Glycoprotein Substrates by Coadministration of Biochanin A

Effects of coadministration of dietary supplement biochanin A (BA) on the pharmacokinetics of three P-glycoprotein substrates, paclitaxel, digoxin, and fexofenadine, were investigated in rats. With BA coadministration, the oral bioavailability and peak plasma concentration were markedly increased by 3.77- and 2.04-fold for paclitaxel, 1.75- and 1.71-fold for digoxin, but were reduced by 0.694- and 0.429-fold for fexofenadine, respectively. Paclitaxel is a Pgp and CYP3A substrate, the drastic increase in systemic exposure may be attributed to the synergistic inhibition of Pgp and CYP3A by BA in the intestine. Digoxin is a substrate for Pgp, CYP3A, and Oatp2. BA may suboptimally inhibit Pgp and CYP3A, resulting in a moderate increase in oral bioavailability of digoxin. Fexofenadine is a substrate for Pgp, Oatp1, Oatp2, and Oatp3. BA appears to preferentially inhibit Oatp3 over Pgp in the intestine, leading to the decreased oral absorption of fexofenadine. No significant changes in mean residence time and terminal half-life were observed for all drugs, suggesting a negligible effect of BA on their hepatic/renal elimination. These findings demonstrate the importance of interplay among uptake/efflux transporters and metabolizing enzymes. The enhanced oral absorption by BA coadministration may be exploited to improve oral bioavailability of Pgp and CYP3A substrate compounds.

The effect of pancreatic and biliary depletion on the in vivo pharmacokinetics of digoxin in pigs

Several transporter systems in the liver and intestine are known to change their expression and function during cholestatic disease states. The objective of the present in vivo study was to investigate the effect of biliary depletion, as a method to mimic cholestasis, on the bioavailability and disposition of digoxin in biliary and pancreatic duct cannulated pigs. The study was divided in two parts. In the first part, a solution of 10μg/kg digoxin was administered intravenously to the cannulated pigs with intact enterohepatic circulation (Control) and during depletion of the bile and pancreatic juice. In the second part, the same dose of digoxin was adminstered intraduodenally with intact enterohepatic circulation (Control) and during depletion of either bile or pancreatic juice or both. Biliary depletion decreased the flow of bile and pancreas juice as well as the amount of digoxin appearing in the bile. Deprivation of both bile and pancreas juice significantly increased the bioavailability of digoxin, the plasma AUC after enteral administration increased from 17.6±4.2nmol/lh (Control) to 29.6±8.3nmol/lh (P<0.05). The biliary clearance decreased significantly, from 0.22±0.11l/h/kg (Control) to 0.04±0.03l/h/kg during pancreatic and biliary depletion (P<0.05). There was a significant decrease in elimination half-life (P<0.05) and volume of distribution (P<0.01) during the depletion experiments while the systemic clearance remained unchanged. The results clearly suggest that biliary depletion trigger a short-term downregulation, most likely posttranscriptionally mediated, of a sinusoidal uptake transporter in the liver, possibly a pig ortholog of OATP.

Modification of the P-Glycoprotein Dependent Pharmacokinetics of Digoxin in Rats by Human Recombinant Interferon-α

This study was conducted to investigate in vivo the impact of interferon-alpha (IFN)-alpha on P-glycoprotein (P-gp) activity in rats by studying how its administration modifies the bioavailability of digoxin, a fairly pure P-gp substrate. Human recombinant IFN-alpha was given to rats (n = 5-7 per group) daily for 8 days at different doses (IntronA) 10(6), 2.10(6), or 4.10(6) IU kg(-1), s.c.), whereas pegylated-IFN-alpha (ViraferonPeg), 29 microg kg(-1)) was given s.c. three times a week. Rats were then given digoxin (32 microg kg(-1)) i.v. or orally. The pharmacokinetics of digoxin was studied. Intestinal P-gp expression was also examined. The pharmacokinetics of i.v. administered digoxin was not modified by IFN-alpha, but a dose-dependent increase in areas under the curve (AUCs) was observed in the orally administered digoxin parameters in rats (AUCs: 392 +/- 83 min microg L(-1), p < 0.01 and 550 +/- 97 min microg L(-1), p < 0.001, respectively, vs. 286 +/- 111 min microg L(-1) for control). A decrease in P-gp expression in the ileum (relative intensities: 0.70 +/- 0.19 for 4 Million International Unit (MIU) kg(-1) IFN-alpha-treated animals vs. 1.00 +/- 0.13 for controls, p < 0.05) and mainly in the jejunum (relative intensities: 0.46 +/- 0.13 for 4 MIU kg(-1) IFN-alpha-treated animals vs. 1.00 +/- 0.08 for controls, p < 0.001) was observed. IFN-alpha induces in vivo a significant dose-dependent inhibitory effect on intestinal P-gp activity related to a local decrease in its expression, thereby predicting important clinical consequences when IFN-alpha and other P-gp substrates are associated.

Heritability of digoxin pharmacokinetics

Background/Aims The clinical significance of genetic variability in membrane transporters is still unclear. In this study, we compared digoxin pharmacokinetics in monozygotic (MZ) and dizygotic (DZ) twin pairs to test the hypothesis that genetic differences contribute to interindividual variability in digoxin disposition. Digoxin is minimally metabolized in humans and its bioavailability is highly dependent on drug transporters. Methods Each twin pair (10 MZ and 6 DZ) was administered a 1 mg oral dose of digoxin and plasma and urine were collected over 3 days. Pharmacokinetic parameters were estimated using standard methods. A preliminary estimate of heritability was calculated using variability between and within the MZ twin pairs (rGC= (Vbetween−Vwithin)/Vbetween). Results Preliminary estimates indicate that 36% of the variability in oral clearance (CL/F) can be attributed to genetics (rGC= 0.359). In contrast, genetics accounts for only a minor component of the variability in CLR (rGC= 0.19). Data from DZ twin pairs will be used to estimate the true heritability index. Conclusions These studies suggest that digoxin oral clearance is influenced by both environmental and genetic differences among individuals. Future studies will determine the contribution of genetic polymorphisms in membrane transporters involved in digoxin bioavailability on interindividual variability in digoxin pharmacokinetics. Clinical Pharmacology & Therapeutics (2005) 77, P21–P21; doi: 10.1016/j.clpt.2004.11.083

ジゴキシン服用入院患者を対象とした錠剤と散剤の血中濃度の比較検討およびその変動要因の評価

The bioavailability of digoxin is known to differ between tablets and powders. To evaluate this difference in clinical practice, serum concentrations were compared between inpatients who received tablets (tablet group) and those who received a powder (powder group). For the powder, the quantity packaged by an automatic packaging machine and that on removal from the package were measured.The C/D (concentration/dose/body weight) in the powder group was significantly less than that in the tablet group when classified according to Ccr (creatinine clearance) and age. The difference in C/D increased with age, and, as compared with the tablet group, there was a 42.2 % greater decrease in C/D in the powder group for those over 80 years old. After removal from the package, the quantity of powder was about 6.1% less than it than that packaged by the automatic packaging machine. In a study using volunteers that was also performed, the powder losses stemming from packaging were 7.3% and 18.0% in young people and the elderly, respectively.These results suggest that the difference in C/D between tablets and the powder stemmed not only from the difference in their bioavailabilities but also from losses arising during preparation and at the time of taking the powder.

Herbal Modulation of P‐Glycoprotein

P‐glycoprotein (Pgp) is a 170 kDa phosphorylated glycoprotein encoded by human MDR1 gene. It is responsible for the systemic disposition of numerous structurally and pharmacologically unrelated lipophilic and amphipathic drugs, carcinogens, toxins, and other xenobiotics in many organs, such as the intestine, liver, kidney, and brain. Like cytochrome P450s (CYP3A4), Pgp is vulnerable to inhibition, activation, or induction by herbal constituents. This was demonstrated by using an ATPase assay, purified Pgp protein or intact Pgp‐expressing cells, and proper probe substrates and inhibitors. Curcumin, ginsenosides, piperine, some catechins from green tea, and silymarin from milk thistle were found to be inhibitors of Pgp, while some catechins from green tea increased Pgp‐mediated drug transport by heterotropic allosteric mechanism, and St. John's wort induced the intestinal expression of Pgp in vitro and in vivo. Some components (e.g., bergamottin and quercetin) from grapefruit juice were reported to modulate Pgp activity. Many of these herbal constituents, in particular flavonoids, were reported to modulate Pgp by directly interacting with the vicinal ATP‐binding site, the steroid‐binding site, or the substrate‐binding site. Some herbal constituents (e.g., hyperforin and kava) were shown to activate pregnane X receptor, an orphan nuclear receptor acting as a key regulator of MDR1 and many other genes. The inhibition of Pgp by herbal constituents may provide a novel approach for reversing multidrug resistance in tumor cells, whereas the stimulation of Pgp expression or activity has implication for chemoprotective enhancement by herbal medicines. Certain natural flavonols (e.g., kaempferol, quercetin, and galangin) are potent stimulators of the Pgp‐mediated efflux of 7,12‐dimethylbenz(a)‐anthracene (a carcinogen). The modulation of Pgp activity and expression by these herb constituents may result in altered absorption and bioavailability of drugs that are Pgp substrates. This is exemplified by increased oral bioavailability of phenytoin and rifampin by piperine and decreased bioavailability of indinavir, tacrolimus, cyclosporine, digoxin, and fexofenadine by coadministered St. John's wort. However, many of these drugs are also substrates of CYP3A4. Thus, the modulation of intestinal Pgp and CYP3A4 represents an important mechanism for many clinically important herb–drug interactions. Further studies are needed to explore the relative role of Pgp and CYP3A4 modulation by herbs and the mechanism for the interplay of these two important proteins in herb–drug interactions.

Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer

P-glycoprotein, encoded by the MDR-1 gene, confers multi-drug resistance against antineoplastic agents and is important for the transmembrane transition of various other common therapeutic drugs. Recently, a number of polymorphisms in the MDR-1 gene were identified and the T/T genotype at position 3435 in exon 26 was found to correlate with intestinal P-glycoprotein expression and bioavailability of digoxin after oral administration. We analysed the allelic frequencies at the polymorphic site C3435T in a group of patients with locally advanced breast cancer treated by preoperative chemotherapy to evaluate its predictive value. Sixty-eight patients diagnosed between 1998 and 2001 were treated by preoperative chemotherapy with anthracyclines or these agents combined with taxanes. From genomic DNA, a 106 bp fragment of MDR-1 exon 26 was amplified and the C3435T genotype was determined by Pyrosequencing methodology. A potential correlation with therapeutic response was calculated with Fisher's exact test. The overall clinical response rate (cCR and cPR) was 68% but only 7 patients (10.3%) achieved pathological complete response (pCR). Heterozygous C3435T occurred in 57% of the subjects and 22% of the analysed individuals possessed only T alleles. Statistical analysis revealed a significant correlation (p=0.029) between clinical complete response to preoperative chemotherapy and the T/T genotype. MDR-1 polymorphism C3435T in exon 26 may co-determine resistance to chemotherapy and provide useful information to individualize therapy.

Clinical pharmacokinetics of atorvastatin.

Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease. Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. The clinical dosage range for atorvastatin is 10-80 mg/day, and it is given in the acid form. Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration. However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98%. Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of atorvastatin acid. In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin. Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3. Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated. An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs. Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.