Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin–clarithromycin interaction

doi:10.1046/j.1365-2125.2003.01824.x

Journal List > Br J Clin Pharmacol > v.56(1); Jul 2003

Br J Clin Pharmacol. 2003 July; 56(1): 32–38.

doi: 10.1046/j.1365-2125.2003.01824.x.

PMCID: PMC1884337

Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin–clarithromycin interaction

Jens Rengelshausen, Christoph Göggelmann, Jürgen Burhenne, Klaus-Dieter Riedel, Jochen Ludwig,¹ Johanna Weiss, Gerd Mikus, Ingeborg Walter-Sack, and Walter E Haefeli

Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany

¹Central Laboratory, Section for Laboratory Medicine, Department of Internal Medicine I, University of Heidelberg, Heidelberg, Germany

Correspondence: Walter E. Haefeli MD, Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Bergheimer Str. 58, D-69115 Heidelberg, Germany. Tel.: + 49 6221 56 8740; Fax: + 49 6221 56 4642; E-mail: walter_emil_haefeli/at/med.uni-heidelberg.de

Received October 13, 2002; Accepted December 19, 2002.

This article has been cited by other articles in PMC.

Abstract

Aims

A clinically important interaction between the cardiac glycoside digoxin and the antibiotic clarithromycin has been suggested in earlier reports. The aim of this study was to investigate the extent of the interaction and the relative contribution of different mechanisms.

Methods

In a randomized, placebo-controlled, double-blind cross-over design single oral doses of 0.75 mg digoxin with oral coadministration of placebo or 250 mg clarithromycin twice daily for 3 days were administered to 12 healthy men. Additionally, three of the subjects received single intravenous doses of 0.01 mg kg⁻¹ digoxin with oral placebo or clarithromycin. Digoxin plasma and urine concentrations were determined by a highly sensitive radioimmunoassay.

Results

Oral coadministration of clarithromycin resulted in a 1.7-fold increase of the area under the digoxin plasma concentration–time curve [mean AUC(0,24) ± SD 23 ± 5.2 vs. 14 ± 2.9 µg L⁻¹ h; 95% confidence interval (CI) on the difference 7.0, 12; P = 0.002] and in a reduction of the nonglomerular renal clearance of digoxin [mean Cl_Rng(0, 24) ± SD 34 ± 39 vs. 57 ± 41 mL min⁻¹; 95% CI on the difference 7.2, 45; P = 0.03]. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption period of clarithromycin. After intravenous administration digoxin AUC(0,24) increased only 1.2-fold during coadministration of clarithromycin.

Conclusions

Increased oral bioavailability and reduced nonglomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P-glycoprotein.

Keywords: bioavailability, clarithromycin, digoxin, drug interactions, human, P-glycoprotein

Introduction

Case reports about patients with digoxin intoxication have suggested an interaction between the cardiac glycoside and the macrolide antibiotics erythromycin and clarithromycin [1, 2]. Erythromycin has been shown to increase serum digoxin concentrations and to decrease the excretion of digoxin metabolites in urine and stool in healthy individuals [3]. Therefore, it has been speculated that erythromycin modifies the gut flora and thus decreases the bacterial digoxin metabolism leading to an increased oral bioavailability of digoxin and increased serum digoxin concentrations. This mechanism is expected to yield a clinically important interaction only in the minority of patients who normally excrete significant amounts of inactive digoxin reduction products [3].

Another mechanism for the interaction between digoxin and clarithromycin may be a decrease in renal tubular digoxin secretion [4]. The latter appears to be mediated by the ATP-dependent export pump P-glycoprotein, an integral membrane protein expressed in the apical surface of tubular epithelia [5, 6]. In the isolated perfused rat kidney, renal tubular secretion of digoxin was inhibited by quinidine and verapamil which are known to inhibit P-glycoprotein and to cause drug interactions with digoxin in patients [7]. Furthermore, clarithromycin inhibited transcellular digoxin transport in a porcine kidney epithelial cell line overexpressing P-glycoprotein, indicating that clarithromycin might inhibit the renal tubular secretion of digoxin [4]. This inhibition may also contribute to an increased digoxin exposure during coadministration of clarithromycin.

We have carried out a prospective, randomized, placebo-controlled, double-blind study to clarify the extent of the interaction between digoxin and clarithromycin and the contribution of oral bioavailability and renal clearance to the interaction in healthy men.

Methods

The study was approved by the Ethics Committee of the Medical Faculty of the University of Heidelberg, and was conducted at the Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology in accordance with the Declaration of Helsinki, as amended in Sommerset West 1996, and the specific legal requirements in Germany.

Study population

Twelve healthy, nonsmoking men participated in the study after they had been fully informed about the study and given written informed consent. None was receiving any other systemic drug treatment from 2 months before until the end of the study. The participants were ascertained to be healthy by medical history, physical examination, laboratory screening including haematological and biochemical blood tests, and a 12-lead electrocardiogram. The mean values ± SD (range) of age, body weight, and body mass index were 28 ± 5.2 (21–39) years, 80 ± 9.8 (68–98) kg, and 24 ± 1.9 (22–28) kg m⁻², respectively.

Oral study design

According to a randomized, placebo-controlled, double-blind cross-over design, each participant received a single oral dose of 0.75 mg digoxin (Lanicor^® tablets; Teofarma srl, Valle Salimbene, Italy) during each of two study periods separated by a wash-out phase of at least 2 weeks. Additionally, each participant received 250 mg clarithromycin (Klacid^® tablets, Abbott GmbH, Wiesbaden, Germany) or matching placebo twice daily for 3 days of each study period (to reach steady-state conditions) in a randomized sequence starting 1 day before digoxin administration. Klacid^® tablets were encapsulated into hard gelatine capsules by the hospital pharmacy to match the corresponding placebo capsules filled with lactose. On the second day of each study period clarithromycin or placebo was ingested 30 min before digoxin administration. To gain a high and constant urine flow, each participant was encouraged to drink at least 200 mL of water every hour on the days of digoxin administration. After an overnight fast from 12 h before until 4 h after digoxin administration, each participant received a standard hospital lunch and dinner served at 4 and 9 h after digoxin dosing. Food or beverages containing alcohol or caffeine were not allowed from 12 h before clarithromycin administration until the last blood sample was drawn. Venous blood samples (7.5 mL each) were collected through an intravenous cannula into heparinized tubes. Blood samples were obtained 30, 20, and 10 min before and 10, 20, 30, 40, 50 min, and 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, and 48 h after each administration of digoxin. Blood samples were immediately centrifuged (3000 g for 10 min at 4 °C). Separated plasma samples were stored at −20 °C until analysis. After completely voiding the bladder immediately before digoxin intake, the participants collected urine in consecutive fractions 2, 4, 6, 8, 10, 12, 24, and 48 h after each administration of digoxin. After measurement of the urine volume, a 10-mL aliquot of each fraction was stored at −20 °C until analysis.

Intravenous study design

A study with intravenous digoxin administration to the 12 participants was planned according to the same design except for the following changes. Instead of oral administration, 0.01 mg kg⁻¹ body weight digoxin (Novodigal^® ampoules, 0.4 mg per 2 mL each; Lilly Deutschland GmbH, Giessen, Germany) was administered intravenously over 4 min. Additionally, 5 g sinistrin (Inutest^® ampoules, 5 g per 20 mL each; Fresenius Kabi Austria GmbH, Linz, Austria) were injected intravenously over 4 min immediately before the digoxin injection to determine accurately the glomerular filtration rate (GFR) [8]. Clarithromycin or placebo was administered 2 h before digoxin administration to reach overlapping peak plasma concentrations of the two compounds [9]. Blood samples were taken from a vein of the forearm contralateral to the injection site 10 and 5 min before and 0, 5, 10, 15, 20, 30, 45 min, and 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, and 72 h after the end of each digoxin administration. Urine was collected in consecutive fractions 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 48 h after each administration of digoxin. The first three participants reported a local burning sensation during the injection of digoxin and developed thrombophlebitis at the injection site. These adverse events were probably related to the consecutive injections of sinistrin and digoxin and disappeared after local treatment. Because of these adverse events the intravenous study was stopped after the third participant.

Determination of digoxin plasma and urine concentrations

Digoxin concentrations in plasma and urine were determined using a competitive solid-phase radioimmunoassay (Digoxin-RIA ¹²⁵I, Coat-A-Count^®; DPC Biermann GmbH, Bad Nauheim, Germany). Calibrations for plasma were done in the range of 0.5–8.0 µg L⁻¹. For concentrations below 0.5 µg L⁻¹ the samples were reassayed with increased sample volume in the range of 0.1–1.0 µg L⁻¹. The lower limit of quantification in plasma was 0.1 µg L⁻¹. The day-to-day coefficient of variation (CV) of spiked quality control plasma samples was 12%, 10% and 11% at concentrations of 1.0, 3.7 and 5.6 µg L⁻¹, respectively. The accuracy was −10%, −6.9% and −4.1% at target concentrations of 1.0, 3.7 and 5.6 µg L⁻¹, respectively. Calibrations for urine were done in the range of 5.0–80 µg L⁻¹. The urine samples were diluted 1 : 10 with human albumin/phosphate buffer pH 7.4. The lower limit of quantification in urine was 5.0 µg L⁻¹. The day-to-day coefficient of variation of spiked quality control urine samples was 11%, 6.7% and 9.6% at concentrations of 9.8, 37 and 56 µg L⁻¹, respectively. The accuracy was −11%, −0.9% and −1.0% at target concentrations of 9.8, 37 and 56 µg L⁻¹, respectively.

Determination of clarithromycin plasma concentrations

Clarithromycin plasma concentrations were determined by LC/MS with atmospheric pressure chemical ionization (APCI) after alkaline liquid/liquid extraction with tert-butyl methyl ether according to [10] with minor modifications. For calibration erythromycin was used as internal standard and the lower limit of quantification was 8.8 µg L⁻¹. The batch-to-batch coefficient of variation of spiked quality control samples was 9.4%, 12% and 9.4% at concentrations of 63, 310, and 1100 µg L⁻¹, respectively. The accuracy was calculated as the difference between given and measured mean clarithromycin concentrations in percent and was 0.0%, +5.4% and +9.0% at target concentrations of 63, 310 and 1100 µg L⁻¹, respectively. The method was linear in the range of 8.8 µg L⁻¹ and 1800 µg L⁻¹ and the coefficients of correlation of the regression lines were always > 0.995.

Determination of creatinine plasma and urine concentrations

For the quantification of creatinine in urine and plasma a selective and sensitive ion pair high-performance liquid chromatography (HPLC)/UV method was used according to [11] with minor modifications. Urine samples were injected onto the HPLC after dilution (1 : 10) with Hanks' balanced salt solution (HBSS) and spiking with internal standard (3-aminotriazole). The limit of quantification was 3.4 mg dL⁻¹. The method is linear in the range of 3.4 and 340 mg dL⁻¹. The accuracy varied from −4.0% to 1.3% (% bias batch-to-batch) and the precision varied between 2.6% and 7.1% (% CV batch-to-batch). Plasma samples were injected into HPLC after precipitation with perchloric acid, spiking with internal standard (3-aminotriazole) and centrifugation. The limit of quantification was 0.1 mg dL⁻¹. The accuracy varied from −4.9% to 0.9% (% bias batch-to-batch) and the precision varied between 2.2% and 8.6% (% CV batch-to-batch). The method was linear in the range of 0.1 and 4.3 mg dL⁻¹.

Determination of sinistrin plasma and urine concentrations

Sinistrin concentrations were determined by an automated enzymatic assay on a Cobas Mira analyser (Roche Diagnostics GmbH, Mannheim, Germany) as previously described [12]. For plasma and urine the limit of quantification was 50 mg L⁻¹. The method was linear between 50 and 1000 mg L⁻¹. For plasma, the accuracy varied from 4.7% to 6.1% (% bias) and the precision varied between 2.3% and 2.6% (% CV). Urine samples were diluted 1 : 10 in a watery solution containing 40 g L⁻¹ bovine serum albumin. For urine, the accuracy varied from −0.1% to 2.4% (% bias) and the precision varied between 2.4% and 3.4% (% CV).

MDR-1 genotyping

The presence of the C3435T polymorphism in exon 26 of the human multidrug resistance gene 1 (MDR-1) encoding P-glycoprotein [13] was determined using the hybridization probes format on the Light Cycler™ (Roche Molecular Biochemicals, Mannheim, Germany) according to the method described by Nauck et al.[14].

Pharmacokinetic analysis

Noncompartmental analysis using WinNonlin 3.1 software (Pharsight Corp., Mountain View, CA, USA) was performed to determine pharmacokinetic parameters of digoxin, clarithromycin, and sinistrin. The peak plasma concentration (C_max) and the time to reach C_max (t_max) were obtained directly from the raw data. Areas under the concentration–time curve [AUC(t₁,t₂)] with t₁ and t₂ as time limits were calculated by the linear trapezoidal rule. Renal clearances of digoxin, creatinine and sinistrin during a time interval t₁–t₂ were calculated as Cl_R(t₁,t₂) = Ae(t₁,t₂)/AUC(t₁,t₂), where Ae(t₁,t₂) is the amount excreted into urine during the time interval t₁–t₂ and AUC(t₁,t₂) is the corresponding partial AUC of either digoxin, creatinine, or sinistrin. The renal clearance of digoxin consists of glomerular filtration, tubular secretion and tubular reabsorption [15]. The amount of digoxin filtered by the glomeruli equals the GFR corrected for the unbound fraction of digoxin (f_u). The nonglomerular renal clearance of digoxin during the first 24 h after digoxin administration was calculated from the equation Cl_Rng(0,24) = Cl_R,Digoxin(0,24) − f_u GFR [16]. Creatinine clearance might overestimate GFR, whereas sinistrin clearance appears to be a more accurate measure of GFR [16]. Owing to a urine collection error, the values for Cl_R(0,24) and Cl_Rng(0,24) could not be calculated in two participants.

Statistical analysis

Data are expressed as mean values ± SD or as mean values ± SEM. Differences in the pharmacokinetic parameters of digoxin between concomitant clarithromycin or placebo treatment were assessed with the nonparametric Wilcoxon signed rank test for paired data including 95% confidence intervals (CI) on differences. A sample size of at least n = 11 was estimated to detect a 50% increase in the digoxin AUC(0,24) with a significance level of 5% and a statistical power of 95%. Digoxin pharmacokinetic parameters in the MDR-1 genotype groups were compared by the nonparametric Wilcoxon rank sum test (Mann–Whitney U-test) for unpaired data. A P-value < 0.05 was considered statistically significant.

Results

The plasma concentration–time profiles of orally administered digoxin with and without concomitant oral clarithromycin are shown in Figure 1. During clarithromycin administration the mean C_max of digoxin was increased 1.8-fold, and the AUC(0,3) and AUC(0,24) 1.7-fold (Table 1). The 15% decrease in Cl_R(0,24) was not significant, whereas the nonglomerular renal clearance Cl_Rng(0,24) was significantly decreased by 41% during clarithromycin administration. Cl_Cr, f_u, and t_max remained unchanged (Table 1). The plasma concentration–time curve of oral clarithromycin on the day of digoxin administration is shown in Figure 2. The ratios of mean digoxin plasma concentrations with and without clarithromycin plotted against the mean plasma concentrations of clarithromycin yielded a clockwise hysteresis (Figure 2) with highest digoxin ratios occurring during the absorption of clarithromycin.

Figure 1

Mean (± SEM) plasma concentration–time curves for oral digoxin (0.75 mg) with coadministration of placebo ( [open circle]

) or clarithromycin (•) in 12 healthy men. Insert: individual and mean (± SEM) values AUC(0,24) of digoxin (more ...)

Table 1

Pharmacokinetic characteristics of a single oral dose of digoxin (0.75 mg) with coadministration of placebo or clarithromycin in 12 healthy men.

Figure 2

Mean (± SEM) plasma concentration–time curve of oral clarithromycin (250 mg) on the second day of administration in 12 healthy men. Insert: ratios of mean plasma concentrations of digoxin with and without clarithromycin plotted against (more ...)

Comparing the plasma digoxin concentration–time curves between intravenous and oral administration in the three individuals participating in both trials (Figure 3), the effect of clarithromycin on digoxin plasma concentrations is more pronounced during oral digoxin administration. With intravenous administration the AUC(0,24) of digoxin was increased only 1.2-fold during administration of clarithromycin (Table 1), and the Cl_R(0,24) was decreased by 12% (130 ± 20 vs. 150 ± 23 mL min⁻¹, n = 3). The absolute difference in Cl_R(0,24) is reflected in the Cl_Rng(0,24) calculated on the basis of Cl_creatinine (40 ± 25 vs. 60 ± 14 mL min⁻¹, n = 3) as well as on the basis of Cl_sinistrin (76 ± 15 vs. 98 ± 21 mL min⁻¹, n = 3).

Figure 3

Mean (± SEM) plasma concentration–time curves of intravenous digoxin (0.01 mg kg⁻¹) (A) and oral digoxin (0.75 mg) (B) during coadministration of placebo ( [open circle]

) or clarithromycin (•) in the three healthy men who participated (more ...)

Determination of the C3435T polymorphism of the MDR-1 gene encoding P-glycoprotein revealed five participants to be C/C, six C/T and one T/T genotypes. Differences were tested between C/C group and the combined C/T and T/T group. No significant association to one of the groups could be found with regard to the absolute differences in AUC(0,24) and C_max of orally administered digoxin between placebo and clarithromycin (10 ± 4.4 vs. 8.6 ± 4.2 µg L⁻¹ h, 95% CI of difference −4.0, 7.5, P = 0.94 and 3.0 ± 1.9 vs. 2.9 ± 1.9 µg L⁻¹, 95% CI of difference −2.9, 2.2, P = 0.68, respectively).

Discussion

Oral coadministration of clarithromycin led to a 1.7-fold increase in the AUC(0,24) of digoxin after single oral administration of a regular 0.75-mg loading dose. Because of dose-independent digoxin pharmacokinetics [17], subsequent maintenance doses are expected to result also in a similar increase in mean steady-state plasma concentrations during prolonged coadministration of clarithromycin, which agrees with clinical case reports [1, 4] and a recent study including seven patients older than 65 years [18]. In the latter a doubling of serum digoxin concentrations was observed.

Two mechanisms have been proposed as causes for the interaction between digoxin and clarithromycin; namely, increased oral bioavailability [1, 2] and decreased renal clearance of digoxin [4]. In the current study, the renal clearance of digoxin was decreased by only 15% with a significant reduction in the nonglomerular renal clearance, which consists predominantly of tubular secretion [15]. This finding supports the concept that clarithromycin reduces the renal tubular transport of digoxin by inhibition of P-glycoprotein [4]. A similar decrease in the renal clearance of digoxin has been observed during coadministration of itraconazole [19]. Assuming that renal clearance accounts for approximately 80% of total digoxin clearance [20], 15% decrease in renal clearance is expected to result in only a 1.14-fold increase in digoxin AUC, which is in agreement with the small AUC increase observed after intravenous administration of digoxin. In contrast, the 15% decrease in renal clearance cannot fully explain the 1.7-fold increase in AUC seen after oral digoxin administration. The difference in the extent of the interaction between intravenous and oral administration is most probably due to an increase in the oral bioavailability of digoxin during the administration of clarithromycin. Because only a minor fraction of digoxin is metabolized by most individuals [21, 22], an increase in intestinal digoxin absorption is the most likely cause for the increased AUC after oral coadministration of clarithromycin.

Inhibition of bacterial digoxin metabolism in the colon has been considered as a major factor for contributing to the enhanced absorption of digoxin by clarithromycin [1, 2]. However, the occurrence of an interaction would be expected in only 10% of individuals, namely those who normally excrete significant amounts of inactive digoxin reduction products [1, 3]. In contrast, the AUC(0,24) of digoxin was increased in all but one of 12 participants who were randomly selected for the present study (Figure 1), suggesting a much higher incidence of the interaction than previously supposed [1]. In line with our findings, a recent prospective study found increased steady-state serum digoxin concentrations in all seven patients during coadministration of clarithromycin [18].

Eubacterium lentum, which is thought to metabolize digoxin [23], occurs predominantly in the colon and is rarely found in the stomach, jejunum and ileum of healthy individuals [24]. Therefore, orally ingested digoxin must reach the colon to be metabolized by the bacterium. If clarithromycin inhibited bacterial metabolism, increased digoxin absorption in the colon would be expected. Assuming a regular orocaecal transit time of 3.5–5 h [25], increased digoxin absorption would not occur earlier than at least 3.5 h after digoxin administration. However, in the present study 25% of the increase in AUC occurred in the first 3 h, indicating that a proportion of the interaction between digoxin and clarithromycin occurs during the absorption of digoxin in the small intestine [26]. Therefore, inhibition of bacterial digoxin metabolism in the colon might be only a minor cause of the interaction.

P-glycoprotein is expressed in the apical membrane of intestinal cells in the small and large bowel [27], and appears to mediate the apical export of digoxin in human intestinal epithelial Caco-2 cell monolayers [28]. Induction of intestinal P-glycoprotein by oral rifampicin coincides with a decrease in the oral bioavailability of digoxin in healthy humans [29], indicating that P-glycoprotein limits the intestinal absorption of digoxin by active transport back into the intestinal lumen. Clarithromycin acts as an inhibitor of P-glycoprotein [4], and thus might increase the intestinal absorption of digoxin. In the present study, the ratio of mean digoxin plasma concentrations with and without clarithromycin was used as a measure of the effect of clarithromycin on digoxin plasma concentrations. As indicated by the clockwise hysteresis (Figure 2), this ratio was highest at initially low plasma concentrations of clarithromycin and decreased at clarithromycin peak concentrations in plasma. This indicates that clarithromycin had its maximal effect on digoxin kinetics at a time when plasma concentrations of the latter were low and high concentrations of clarithromycin were present at the intestinal wall. Such a mechanism does not preclude an additional contribution of renal P-glycoprotein to the interaction, but the decrease in the effect on digoxin when plasma clarithromycin concentrations were still increasing is in agreement with the hypothesis that presystemic intestinal P-glycoprotein contributes substantially to this interaction.

The single nucleotide polymorphism C3435T in exon 26 of the human multidrug resistance gene 1 (MDR-1) encoding P-glycoprotein has been shown to correlate with its intestinal expression, and intestinal digoxin uptake in humans [13]. In a recent study the influence of two MDR-1 polymorphisms (C3435T and the polymorphism G2677T in exon 21) on the bioavailability of digoxin and on the interaction between digoxin and clarithromycin was investigated in healthy Asians [30]. Only in the group homozygous for the ‘wild-type’ allele of both polymorphisms (G/G2677 and C/C3435) was digoxin oral bioavailability significantly increased during administration of clarithromycin. In contrast to these findings, there was no significant effect of the C3435T polymorphism on the differences in digoxin AUC(0,24) and C_max during clarithromycin in the present study. The small sizes of the genotypic groups limit the interpretation of genetic influences in both studies. However, in contrast to the previous study [30], we used the same digoxin dosage in both treatment groups and also a randomized, placebo-controlled, double-blind design enabling a reliable systematic comparison of digoxin pharmacokinetics during administration of either placebo or clarithromycin.

In conclusion, concomitant oral administration of clarithromycin results in a significant and probably clinically relevant increase in systemic digoxin exposure after oral administration. Increased oral bioavailability and decreased nonglomerular renal clearance of digoxin both contribute to the interaction, probably due to inhibition of intestinal and renal P-glycoprotein by oral clarithromycin. Because the interaction is expected to occur in the majority of individuals, patients treated concurrently with oral digoxin and clarithromycin should be closely monitored.

Acknowledgments

This study was supported by grant 01EC9902 of the German Federal Ministry of Research and Education (BMBF) and by the Hans-Dengler-Research-Scholarship for Clinical Pharmacology 2000 of the University of Heidelberg. We thank Mrs Dorothea Schimpf MSc for preparing the study medication, Mrs Brigitte Tubach for study support and Mrs Jutta Kocher, Mrs Magdalena Longo and Mrs Andrea Deschlmayr for their excellent technical assistance.

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