Grapefruit Juice Enhances the Exposure to Oral Oxycodone

Abstract: Grapefruit juice alters the concentrations of many CYP3A substrates. The objective of this study was to examine the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral oxycodone in a randomized cross‐over study with two phases at an interval of 4 weeks. Twelve healthy volunteers ingested 200 ml of grapefruit juice or water t.i.d. for 5 days. An oral dose of oxycodone hydrochloride 10 mg was administered on day 4. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed from the plasma samples for 48 hr and behavioural and analgesic effects were recorded for 12 hr. Grapefruit juice increased the mean area under the oxycodone concentration–time curve (AUC_0–∞) by 1.7‐fold (p < 0.001), the peak plasma concentration by 1.5‐fold (p < 0.001) and the half‐life of oxycodone by 1.2‐fold (p < 0.001) as compared to the water. The metabolite‐to‐parent AUC_0–∞ ratios (AUC_m/AUC_p) of noroxycodone and noroxymorphone decreased by 44% (p < 0.001) and 45% (p < 0.001), respectively. Oxymorphone AUC_0–∞ increased by 1.6‐fold (p < 0.01) after grapefruit juice, but the AUC_m/AUC_p remained unchanged. Pharmacodynamic changes were modest and only self‐reported performance significantly impaired after grapefruit juice. Analgesic effects were not influenced. Grapefruit juice inhibited the CYP3A4‐mediated first‐pass metabolism of oxycodone, decreased the formation of noroxycodone and noroxymorphone and increased that of oxymorphone. We conclude that dietary consumption of grapefruit products may increase the concentrations and effects of oxycodone in clinical use.     

Grapefruit juice can increase the plasma concentrations of oral methylprednisolone

Objective: To investigate whether the pharmacokinetics of orally administered methylprednisolone and plasma cortisol concentrations are affected by administration of grapefruit juice. Methods: In a randomised, two-phase, cross-over study, ten healthy subjects received either 200 ml double-strength grapefruit juice or water three times a day for 2 days. On day 3, 16 mg methylprednisolone was given orally with 200 ml grapefruit juice or water. Additionally, 200 ml grapefruit juice or water was ingested 0.5 h and 1.5 h after methylprednisolone administration. Plasma concentrations of methylprednisolone and cortisol were determined using liquid chromatography/mass spectrometry (LC/MS/MS) over a 47-h period. Results: Grapefruit juice increased the total area under the plasma methylprednisolone concentration–time curve (AUC_0–∞) by 75% (P < 0.001) and the elimination half-life (t _1/2) of methylprednisolone by 35% (P < 0.001). The peak plasma concentration of methylprednisolone (C_max) was increased by 27% (P < 0.01). Grapefruit juice delayed the time to the C_max from 2.0 h to 3.0 h (P < 0.05). There was no significant difference in the plasma cortisol concentrations, measured after methylprednisolone administration, between the water and grapefruit juice phases. However, grapefruit juice slightly decreased the morning plasma cortisol concentrations before methylprednisolone administration (P < 0.05). Conclusions: Grapefruit juice given in high amounts moderately increases the AUC_0–∞ and t _1/2 of oral methylprednisolone. The increase in t _1/2 suggests that grapefruit juice can affect the systemic methylprednisolone metabolism. The clinical significance of the grapefruit juice–methylprednisolone interaction is small, but in some sensitive subjects high doses of grapefruit juice might enhance the effects of oral methylprednisolone. Received: 17 February 2000 / Accepted in revised form: 9 May 2000     

Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects

Aim

This study examined the effects of grapefruit juice on the new P2Y₁₂ inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein.

Methods

In a randomized crossover study, 10 healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90 mg dose of ticagrelor.

Results

Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (C_max) to 165% (95% confidence interval 147, 184%) and area under the concentration–time curve (AUC(0,∞)) to 221% of control (95% confidence interval 200, 245%). The C_max and AUC(0,34 h) (P < 0.05) but not the AUC(0,∞) of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity.

Conclusions

Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice–ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.     

Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy male volunteers

Purpose

Icotinib hydrochloride {4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), was designed for the treatment of non-small cell lung cancer (NSCLC). In the present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3 alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers.

Methods

In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers received an oral dose of 600?mg of icotinib. Plasma was sampled for up to 72?h post-dose, followed by quantification of icotinib by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS-MS).

Results

Five subjects genotyped as homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria. The mean icotinib AUC_0-∞ and C_max (14.56 ±5.31?h?mg/L and 2.32?±?0.49?μg/mL) in homozygous EMs was 1.56 and 1.41-fold lower than that in heterozygous EMs (22.7?±?6.11 and 3.28?±?0.48, P?=?0.046 and 0.047). The mean CL/F (44.18?±?12.17?L/h) in homozygous EMs was 1.55-fold higher than that in heterozygous EMs (28.42?±?9.23?L/h, P?=?0.013).

Conclusions

The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.     

Interaction of citrus juices with pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy subjects

Objectives: The study was conducted to investigate whether oral co-administration with citrus juices significantly affects the pharmacokinetics and/or pharmacodynamics of pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy male subjects. Grapefruit juice and orange juice, which were both commercially available, were used in this study. Methods: Sixteen healthy male Japanese subjects participated in this study and were divided into two groups for grapefruit juice and orange juice treatment. The study followed an open-labelled crossover design, comparing the effects of a single oral dose of 2?mg pranidipine taken together with 250?ml citrus juice or 250?ml water. Serum pharmacokinetics of pranidipine, adverse reactions, blood pressure, heart rate, 12-lead ECG, haematology, clinical chemistry and urinalysis were measured throughout the study. Results: For grapefruit juice, mean C_max and AUC_0–24?h were significantly higher than those of water (P?=?0.0003 and 0.0005, respectively, ANOVA) with the ratios of log transformed values being 1.50?and 1.74, respectively. There were no differences in t_max and t_½ between the juice and water treatments. A significant increase in heart rate (P?=?0.0240, ANOVA with repeated measurements) was observed in the juice treatment whereas there were no significant differences in systolic and diastolic blood pressure between the two treatments. For orange juice, a small decrease in mean C_max was observed compared with water (P?=?0.0218, ANOVA) with the ratio being 0.86, but there was no significant difference in AUC_0–24?h between the two treatments. No marked differences were observed in t_max and t_½. Oral pranidipine administration with orange juice did not affect heart rate, systolic and diastolic blood pressures or other parameters for safety evaluation. Conclusions: Oral co-administration with grapefruit juice and pranidipine was associated with increased bioavailability and changed the pharmacodynamics of pranidipine, particularly with regard to heart rate. Orange juice intake with pranidipine did not markedly affect the pharmacokinetics and no clinically significant changes were observed in the pharmacodynamics and safety evaluation.     

Differences in lercanidipine systemic exposure when administered according to labelling: in fasting state and 15 minutes before food intake

Purpose

The aim of this study was to compare the systemic exposure of lercanidipine (Zanidip) after oral administration in the fasted state and 15?min before food intake (meals) to investigate if the recommendations in the Summary of Product Characteristics (SPC) with respect to the intake of meals are adequate.

Methods

The results of three pilot bioequivalence studies performed to develop a lercanidipine generic product, where Zanidip was administered consistently as reference product in the fasted state or 15?min before a standard breakfast, were compared to estimate the drug–food interaction and the similarity of the methods of administration defined in the SPC.

Results

The ingestion of a standard (non-high-fat, non-high-calorie) meal 15?min after drug intake increased the area under the concentration–time curve (AUC_0-t) of S-lercanidipine by 1.78-fold [90% confidence interval (CI) 1.48–2.15, P?max) of S-lercanidipine by 1.82-fold (90% CI 1.46–2.28, P?Conclusions As intake with a carbohydrate-rich meal is not recommended in the SPC of Zanidip because a twofold difference was considered to be clinically relevant, the intake of lercanidipine only 15?min before food intake does not seem to be consistent with this recommendation. The Marketing Authorisation Holder should clarify the dosing instructions in relation to meals and identify a sufficient time-lapse to ensure an exposure similar to that obtained in phase III clinical efficacy studies.     

Relevance of PepT1 in the Intestinal Permeability and Oral Absorption of Cefadroxil

Purpose

To determine the contribution of intestinal PepT1 on the permeability and oral absorption of the β-lactam antibiotic drug cefadroxil.

Methods

The effective permeability (P _eff ) of cefadroxil was evaluated in wild-type and PepT1 knockout mice following in situ single-pass intestinal perfusions. The plasma concentration-time profiles of cefadroxil were also examined after oral gavage.

Results

The P _eff (cm/s) of cefadroxil in wild-type mice was 0.49?×?10^?4 in duodenum, 0.80?×?10^?4 in jejunum, 0.88?×?10^?4 in ileum and 0.064?×?10^?4 in colon. The P _eff (cm/s) in PepT1 knockout mice was significantly reduced in small intestine, but not in colon, as shown by values of 0.003?×?10^?4, 0.090?×?10^?4, 0.042?×?10^?4 and 0.032?×?10^?4, respectively. Jejunal uptake of cefadroxil was saturable (Km?=?2–4 mM) and significantly attenuated by the sodium-proton exchange inhibitor 5-(N,N-dimethyl)amiloride. Jejunal permeability of cefadroxil was not affected by L-histidine, glycine, cephalothin, p-aminohippurate or N-methylnicotinamide. In contrast, cefadroxil permeability was significantly reduced by glycylproline, glycylsarcosine, or cephalexin. Finally, PepT1 ablation resulted in 23-fold reductions in peak plasma concentrations and 14-fold reductions in systemic exposure of cefadroxil after oral dosing.

Conclusions

The findings are definitive in demonstrating that PepT1 is the major transporter responsible for the small intestinal permeability of cefadroxil as well as its enhanced oral drug performance.     

Rifampicin markedly decreases the exposure to oral and intravenous tramadol

Purpose

Tramadol is mainly metabolized by the cytochrome P450 (CYP) 2D6, CYP2B6 and CYP3A4 enzymes. The aim of this study was to evaluate the effect of enzyme induction with rifampicin on the pharmacokinetics and pharmacodynamics of oral and intravenous tramadol.

Methods

This was a randomized placebo-controlled crossover study design with 12 healthy subjects. After pretreatment for 5 days with rifampicin (600 mg once daily) or placebo, subjects were given tramadol either 50 mg intravenously or 100 mg orally. Plasma concentrations of tramadol and its active main metabolite O-desmethyltramadol (M1) were determined over 48 h. Analgesic and behavioral effects and whole blood 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured.

Results

Rifampicin reduced the mean area under the time–concentration curve (AUC_0-∞) of intravenously administered tramadol by 43 % and that of M1 by 58 % (P?<?0.001); it reduced the AUC_0-∞ of oral tramadol by 59 % and that of M1 by 54 % (P?<?0.001). Rifampicin increased the clearance of intravenous tramadol by 67 % (P?<?0.001). Bioavailability of oral tramadol was reduced by rifampicin from 66 to 49 % (P?=?0.002). The pharmacological effects of tramadol or whole blood serotonin concentrations were not influenced by pretreatment with rifampicin.

Conclusions

Rifampicin markedly decreased the exposure to tramadol and M1 after both oral and intravenous administration. Therefore, rifampicin and other potent enzyme inducers may have a clinically important interaction with tramadol regardless of the route of its administration.     

Effects of one-time apple juice ingestion on the pharmacokinetics of fexofenadine enantiomers

Purpose

We examined the effect of a single apple juice intake on the pharmacokinetics of fexofenadine enantiomers in healthy Japanese subjects.

Methods

In a randomized two phase, open-label crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or apple juice. For the uptake studies, oocytes expressing organic anion-transporting polypeptide 2B1 (OATP2B1) were incubated with 100 μM (R)- and (S)-fexofenadine in the presence or absence of 10 % apple juice.

Results

One-time ingestion of apple juice significantly decreased the area under the plasma concentration–time curve (AUC_0–24) for (R)- and (S)-fexofenadine by 49 and 59 %, respectively, and prolonged the time to reach the maximum plasma concentration (t _max) of both enantiomers (P?R)- and (S)-fexofenadine excretion into urine (Ae_0–24) by 54 and 58 %, respectively, the renal clearances of both enantiomers were unchanged between the control and apple juice phases. For in vitro uptake studies, the uptake of both fexofenadine enantiomers into OATP2B1 complementary RNA (cRNA)-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for (R)-fexofenadine. In addition, apple juice significantly decreased the uptake of both enantiomers into OATP2B1 cRNA-injected oocytes.

Conclusions

These results suggest that OATP2B1 plays an important role in the stereoselective pharmacokinetics of fexofenadine and that one-time apple juice ingestion probably inhibits intestinal OATP2B1-mediated transport of both enantiomers. In addition, this study demonstrates that the OATP2B1 inhibition effect does not require repeated ingestion or a large volume of apple juice.     

Pharmacokinetics and penetration of moxifloxacin into infected diabetic foot tissue in a large diabetic patient cohort

Objectives

Physiological changes occurring in patients with diabetes may affect the pharmacokinetics and penetration of antimicrobial agents into peripheral tissue. We examined the pharmacokinetics and the penetration of moxifloxacin into perinecrotic tissue of diabetic foot lesions in patients with diabetic foot infections (DFI).

Patients and methods

Adult patients suffering from type 2 diabetes mellitus and hospitalized for DFI (Texas classification of at least B2) were treated with 400?mg moxifloxacin intravenously (IV) or orally (PO) once daily. The pharmacokinetics of moxifloxacin and its concentration 3 h after administration in samples of perinecrotic tissue resected from infected diabetic foot wounds were determined at steady state (days 4?C8).

Results

A total of 53 patients with diabetes mellitus type 2 (mean age 69.4?±?10.8?years) were included in the study, of whom 28 received PO and 25 IV moxifloxacin therapy for a median of 8?days. In the PO and IV subgroups, the mean maximum observed plasma concentration (C _max) in plasma was 2.69 and 4.77?mg/l at a median of 2 [time to reach C _max (T _max) range 1.0?C8.0?h] and 1?h after administration, respectively. A mean area under the plasma concentration?Ctime curve from time 0 until the last quantifiable plasma concentration (AUC_0-24?h) of 29.36?mg h/l (PO) and 27.09?mg h/l (IV) was achieved. Mean moxifloxacin concentrations in perinecrotic tissue of infected diabetic foot wounds following PO or IV administration were 1.79?±?0.82?and 2.20?±?1.54???g/g, thus exceeding the MIC₉₀ (minimum inhibitory concentration required to inhibit growth of 90% of organisms) for Staphylococcus aureus (0.25?mg/l) by seven- and eightfold and the MIC₉₀ for Escherichia coli (0.06?mg/l) by 29-fold and 36-fold, respectively. The mean tissue-to-plasma ratios of moxifloxacin concentration 3?h after administration were 1.01?±?0.57 (PO) and 1.09?±?0.69 (IV). Significant differences between the routes of administration were observed for T _max and C _max (P?<?0.01), but not for other clinically relevant parameters (AUC_0-24; moxifloxacin DFI tissue concentration).

Conclusions

The plasma concentration?Ctime curve of moxifloxacin in diabetic patients is similar to that of healthy volunteers. We also observed a good penetration of moxifloxacin into inflamed DFI tissue which taken together with the possibility of sequential IV/PO therapy suggest that moxifloxacin 400?mg once daily is a therapeutic option in the treatment of DFI caused by susceptible organisms.     

Effect of grapefruit juice and food on the pharmacokinetics of pirfenidone in healthy Chinese volunteers: a diet–drug interaction study

1.?Ingestion of grapefruit juice and food could be factors affecting the pharmacokinetics of pirfenidone, a promising drug for treatment of idiopathic pulmonary fibrosis.

2.?A randomized, open-label, three-period crossover study was carried out in 12 healthy Chinese male volunteers who were randomized to one of the three treatments: pirfenidone tablets (0.4?g) were orally administered to fasted or fed subjects, or with grapefruit juice. The washout period was 7 d.

3.?Significantly reduced maximum plasma concentration (C_max, 5.0 5?±?1.39 versus 10.9 0?±?2.94?mg·L^{? 1}), modestly affected area-under-the-plasma concentration–time curve (AUC) from time zero to 12?h post dosing (AUC_0–12?h, 21.8 9?±?6.47 versus 26.1 6?±?7.32?mg·h·L^{? 1}) and delayed time to reach C_max (T_max) were observed in fed group compared with fasted group. Similar effects on C_max (5.8 2?±?1.23 versus 10.9 0?±?2.94?mg·L^{? 1}) and AUC_0–12?h (modest but not statistically significant, 24.4 4?±?7.40 versus 26.1 6?±?7.32?mg·h·L^{? 1}) were observed for grapefruit juice compared to fasted subjects.

4.?Co-administration of pirfenidone with grapefruit juice resulted in modestly reduced overall oral absorption and significantly reduced peak concentrations compared to fasting, which was similar to effect of food ingestion. No adverse events were observed in the study, but relatively dramatic reduction of peak concentrations should raise concerns for clinical efficacy and safety.     

Effects of dosing interval on the pharmacokinetic and pharmacodynamic interactions between the oral adsorbent AST-120 and triazolam in humans

Objective

The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic interactions between the oral adsorbent AST-120 and triazolam.

Methods

In this randomized, cross-over study, 12 healthy volunteers received a single oral dose of triazolam 0.25?mg alone or with AST-120 2?g given 0, 30 or 60?min before triazolam administration.

Results

The area under the plasma triazolam concentration–time curve (AUC_0-∞) significantly decreased with simultaneous AST-120?+?triazolam (alone vs simultaneous: 10.9?±?6.0 vs 6.4?±?2.6?ng·h/mL, p?=?0.003). Triazolam-induced impairment in psychomotor performance assessed by the digit symbol substitution test was significantly attenuated when AST-120 was administered simultaneously. No significant changes in pharmacokinetic and pharmacodynamic parameters were observed when AST-120 was given 30 or 60?min before triazolam administration.

Conclusions

Administering AST-120 simultaneously with triazolam affects the pharmacokinetics and pharmacodynamics of triazolam. Dosing AST-120 at least 30?min before triazolam administration may avoid these interactions.     

Lack of effect of continuous glycyrrhizin administration on the pharmacokinetics of the P-glycoprotein substrate talinolol in healthy volunteers

Purpose

To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of talinolol, a probe drug for P-glycoprotein (P-gp) activity in humans.

Methods

Fourteen healthy adult male subjects were enrolled in a two-phase randomized crossover-design study. In each phase the volunteers received placebo or compound glycyrrhizin tablets (75 mg glycyrrhizin three times daily) for 6 days. On the seventh day, a single oral dose of 100 mg talinolol was administered, and blood samples were obtained to determine plasma talinolol concentrations, measured in plasma by high-performance liquid chromatography with an ultraviolet detector. Non-compartmental analysis was used to characterize talinolol plasma concentration–time profiles. All pharmacokinetics parameters were calculated using DAS ver. 2.1 software, and statistical analyses were performed with SPSS ver. 13.0 software. Analysis of variance was used to check the difference of the means of the pharmacokinetic parameters between the two treatments at a significance level of 0.05.

Results

All treatments were well tolerated during the study period. The geometric mean ± standard deviation of the AUC_0–∞ for talinolol treated by glycyrrhizin and talinolol treated by placebo was 2,218.3?±?724.3 and 1,988.2?±?649.2 ng·h/mL, respectively. The 90 % confidence intervals for the ratio of adjusted geometric means (glycyrrhizin:placebo) for AUC_0–∞ and C _max fell wholly within the interval [80, 125]. Six days of glycyrrhizin treatment resulted in no significant alterations in the pharmacokinetic parameters (AUC_0–∞, AUC_0–24, C _max, t _max, t _½) for talinolol.

Conclusions

Continuous glycyrrhizin administration had no induction effect on the expression of P-gp in our trial. Further research is needed to study the direct inhibition effect of glycyrrhizin on the function of P-gp with the simultaneous administration of both glycyrrhizin and P-gp substrate.     

Significance of trough monitoring for tacrolimus blood concentration and calcineurin activity in adult patients undergoing primary living-donor liver transplantation

Purpose

Tacrolimus pharmacokinetics and calcineurin activity in peripheral blood mononuclear cells (PBMCs) were investigated in adult patients undergoing primary living-donor liver transplantation (LDLT) in order to clarify the significance of monitoring the tacrolimus blood trough concentration during the early post-transplantation period.

Methods

Fourteen patients were enrolled in this study, and time-course data following the oral administration of a conventional tacrolimus formulation twice daily were obtained at 1 and 3?weeks post-transplantation. The concentration of tacrolimus in whole blood and calcineurin activity in PBMCs were measured.

Results

The apparent clearance of tacrolimus significantly increased at 3?weeks versus 1?week post-transplantation, although the trough concentration did not significantly differ at these time points. The concentration at each sampling time, except at 1?h post-dose, correlated well with the area under the concentration?Ctime curve from 0 to 12?h (AUC_0?C12). Neither the concentration at the trough time point nor AUC_0?C12 was correlated with the area under the calcineurin activity?Ctime curve from 0 to 12?h; however, calcineurin activity at the trough time point was strongly correlated with the latter (r ²?>?0.92).

Conclusions

Based on these results, trough concentration monitoring can be considered an appropriate procedure for routine tacrolimus dosage adjustment in adult LDLT patients. Monitoring of calcineurin activity at the trough time point was also found to be potentially useful for predicting the immunological status of the patient during the tacrolimus dosing interval.     

The effect of genetic polymorphisms in UGT2B15 on the pharmacokinetic profile of sipoglitazar, a novel anti-diabetic agent

Purpose

Sipoglitazar was a novel, azolealkanoic acid derivative that possesses selective activity for the peroxisome proliferator-activated receptors (PPAR) PPARγ, PPARα, and PPARδ. The compound undergoes phase II biotransformation by conjugation catalyzed by UDP-glucuronosyltransferase (UGT). The aim of this analysis was to explore the influence of genetic polymorphism in UGT on the pharmacokinetics of sipoglitazar.

Methods

Three preliminary phase I clinical pharmacology studies were conducted in tandem in healthy human subjects. Genotyping was undertaken in a total of 82 subjects in the phase I program for the purpose of genotyping UGT polymorphisms. Plasma samples were collected for up to 48 h post-dose to characterize the pharmacokinetic profile following a single oral dose of the drug.

Results

Plasma concentrations of sipoglitazar and the distribution of dose-normalized individual values for area under the plasma concentration–time curve from time 0 to infinity (AUC_0-∞) before any stratification were considerably skewed with a multi-modal distribution. The proportion of variability in AUC_0-∞ explained by UGT2B15 was 66.7 % (P?<?0.0001); the addition of other genetic or demographic factors was not statistically significant. Subjects homozygous for the UGT2B15 D85Y variant (UGT2B15*2/*2) were exposed to greater plasma concentrations of sipoglitazar than subjects homozygous for the wild-type allele UGT2B15*1/*1 (3.26-fold higher) or heterozygous allele UGT2B15*1/*2 (2.16-fold higher).

Conclusions

These results indicate that sipoglitazar clearance is substantially modified by UGT2B15 enzyme variants, with higher exposure observed in the UGT2B15*2/*2 genotype group.     

Effect of gemfibrozil on the pharmacokinetics of pioglitazone

Objective

Our objective was to study the effects of gemfibrozil on the pharmacokinetics of pioglitazone and the active compounds, which are all the substrates of CYP2C8 and CYP3A4.

Methods

In a randomized, two-phase crossover study, 10 healthy volunteers were pretreated for 2 days with either 600 mg oral gemfibrozil or placebo twice daily. On day 3, they received a single dose of 600 mg gemfibrozil or placebo, and 1 h later they received a single oral dose of 30 mg pioglitazone. Plasma concentrations of pioglitazone and both active metabolites M-III and M-IV were measured for up to 120 h.

Results

Gemfibrozil raised the mean total area under the concentration-time curve (AUC) of parent pioglitazone 3.4-fold (P<0.001). No statistically significant changes were seen in the total AUC of M-III or M-IV after gemfibrozil pretreatment. Gemfibrozil reduced the M-III/pioglitazone and M-IV/pioglitazone AUC_0–∞ ratio by 71% (P<0.001) and 65%(P<0.001), strikingly prolonging their t_½.

Conclusion

Gemfibrozil greatly increased the plasma concentration of parent pioglitazone and also inhibited the further metabolism of M-III and M-IV. Careful blood glucose monitoring and dosage adjustments are suggested during coadministration of pioglitazone and gemfibrozil.     

Pharmacokinetics and pharmacodynamics of single-dose oral tolvaptan in fasted and non-fasted states in healthy Caucasian and Japanese male subjects

Purpose

To compare the pharmacokinetics and pharmacodynamics of tolvaptan in Caucasian and Japanese healthy male subjects under fasting and non-fasting conditions.

Methods

This was a single-center, parallel-group, randomized, open-label, three-period crossover trial of single oral doses of tolvaptan 30?mg under fasting and non-fasting [a high-fat, high-calorie meal (HFM) or Japanese standard meal] conditions in 25 healthy male Caucasian subjects and 24 healthy male Japanese subjects. Pharmacodynamic endpoints were urine volume and fluid balance for 0 to 24?h postdose.

Results

In the fasted state, the plasma tolvaptan C_max and AUC_∞ geometric mean ratios (90 % confidence interval) were 1.105 (0.845–1.444) and 1.145 (0.843–1.554) for Japanese compared to Caucasian subjects. A HFM increased the C_max and AUC_∞ values by about 1.15-fold in both Japanese and Caucasian subjects.. Twenty-four-hour urine volumes paralleled pharmacokinetic changes, but the increases were not clinically significant. Fluid balance in the Japanese men was 1.4- to 2.0-fold more negative than that in the Caucasian men.

Conclusion

Tolvaptan pharmacokinetics is not clinically significantly affected by race. Body weight is a factor that affects exposure. Tolvaptan can be administered with or without food.     

In Vitro and In Vivo Characterisation of PEG-Lipid-Based Micellar Complexes of Salmon Calcitonin for Pulmonary Delivery

Purpose

To investigate DSPE-PEG₂₀₀₀-based micellar formulations of salmon calcitonin (sCT) for their ability to improve pulmonary delivery.

Methods

Micelles were characterised by DLS and ³¹P-NMR spectroscopy. Stability against sCT degrading peptidases, trypsin, ??-chymotrypsin and neutrophil elastase as well as their influence on transepithelial absorption was investigated in vitro. In vivo perfomance of sCT micelles was studied in an experimental model of intratracheal aerosolisation into rats.

Results

Micelles with a mean hydrodynamic diameter of 12?nm spontaneously assembled, when a total concentration of 0.02?mM of PEG-lipid and sCT (at 1:1 molar ratio) was exceeded. Nuclear magnetic resonance confirmed the presence of small micellar structures. The micellar formulation showed increased stability against enzymatic digestion. In vitro studies also showed that sCT micelles were able to enhance transepithelial absorption. Data obtained from in vivo experiments provided evidence of significantly (P?AUC _inf and a relative bioavailability of 160?±?55% when compared to plain sCT solution.

Conclusions

The herein described PEG-lipid micelles are promising carriers for enhanced pulmonary delivery of sCT.     

Effect of Stabilizer on the Maximum Degree and Extent of Supersaturation and Oral Absorption of Tacrolimus Made By Ultra-Rapid Freezing

Purpose

Solid dispersions containing various stabilizers and tacrolimus (TAC) prepared by an Ultra-rapid Freezing (URF) process were investigated to determine the effect on their ability to form supersaturated solutions in aqueous media and on enhancing transport across biological membranes.

Materials and Methods

The stabilizers included poly(vinyl alcohol; PVA), poloxamer 407 (P407), and sodium dodecyl sulfate (SDS). In vivo absorption enhancement in rats was also investigated. Dissolution studies were conducted at supersaturated conditions in both acidic media for 24 h and at delayed release (enteric) conditions to simulate intestinal transit.

Results

The rank order of C/Ceq_max in the dissolution studies at acidic conditions was URF-P407?>?URF-SDS?>?Prograf® (PRO)?>?URF-PVA:P407. For C/Ceq_max under enteric conditions, the order was URF-SDS?>?PRO?>?URF-PVA:P407?>?URF-P407, and for the extent of supersaturation (AUC) in acidic and pH shift conditions it was URF-SDS>PRO>URF-PVA:P407>URF-P407. The pharmacokinetic data suggests URF-P407 had the greatest absorption having higher C _max with a 1.5-fold increase in AUC compared to PRO. All URF compositions had a shorter T _max compared to PRO.

Conclusions

The nanostructured powders containing various stabilizing polymers formed by the URF process offer enhanced supersaturation characteristics leading to increased oral absorption of TAC.     

The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions

Rationale

Both glutamate and serotonin (5-HT) play a key role in the pathophysiology of emotional biases. Recent studies indicate that the glutamate N-methyl-d-aspartate (NMDA) receptor antagonist ketamine and the 5-HT receptor agonist psilocybin are implicated in emotion processing. However, as yet, no study has systematically compared their contribution to emotional biases.

Objectives

This study used event-related potentials (ERPs) and signal detection theory to compare the effects of the NMDA (via S-ketamine) and 5-HT (via psilocybin) receptor system on non-conscious or conscious emotional face processing biases.

Methods

S-ketamine or psilocybin was administrated to two groups of healthy subjects in a double-blind within-subject placebo-controlled design. We behaviorally assessed objective thresholds for non-conscious discrimination in all drug conditions. Electrophysiological responses to fearful, happy, and neutral faces were subsequently recorded with the face-specific P100 and N170 ERP.

Results

Both S-ketamine and psilocybin impaired the encoding of fearful faces as expressed by a reduced N170 over parieto-occipital brain regions. In contrast, while S-ketamine also impaired the encoding of happy facial expressions, psilocybin had no effect on the N170 in response to happy faces.

Conclusion

This study demonstrates that the NMDA and 5-HT receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the N170. These findings suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced changes in emotional processing biases and thus provides a framework to study the pathophysiology of dysfunctional emotional biases.