Aliment Pharmacol Ther 2005; 21: 709–721. doi: 10.1111/j.1365-2036.2005.02385.

Bioequivalence of a new liquid formulation of ursodeoxycholic acid

(Ursofalk suspension) and Ursofalk capsules measured by plasma
pharmacokinetics and biliary enrichment
K. D. R. SETCH ELL*, L. GALZIG NA , N . O ’CONNELL*, G. BRUN ETTIà & H .-D. TAUSCH EL§
*Department of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;  Clinical Biochemistry
Department of Laboratory Medicine, University of Padova, Padova, Italy; àKnoll Farmaceutici, Milan, Italy; §Dr Falk
Pharma, Freiburg, Germany
Accepted for publication 20 December 2004

liquid chromatography and in plasma by mass

SUMMARY
spectrometry.
Background: Ursodeoxycholic acid is an approved ther- Results: The mean percentage biliary ursodeoxycholic
apy for hepatobiliary disorders but in infants and acid enrichment after administration of the suspension
children compliance is compromised because it is was not significantly different from that obtained with
formulated exclusively as capsules, or tablets. capsules (44.2 ± 11.7% vs. 46.9 ± 10.2%, respectively).
Aim: To determine the pharmacokinetics and bioequiv- The equivalence ratio was 0.94 (95% CI: 0.8–1.1),
alence of a new liquid formulation of ursodeoxycholic establishing bioequivalence between suspension and
acid (Ursofalk suspension) with a standard capsule capsules. Both formulations reduced the biliary hydro-
(Ursofalk) in a randomized, unblinded, crossover phobicity index and no differences in bile acid composi-
designed study of 24 healthy adults. tion were observed between formulations. The plasma
Methods: Equivalence was based on single bolus pharmacokinetics of both formulations was similar and
oral plasma pharmacokinetics and biliary ursode- the tolerability of the suspension was excellent.
oxycholic acid enrichments after repeat doses. Bil- Conclusions: A new liquid formulation of ursodeoxy-
iary bile acid composition and hydrophobicity index cholic acid suitable for paediatric patients is pharmaco-
were also compared. Ursodeoxycholic acid was logically bioequivalent to capsules when given as single,
measured in duodenal bile by high-performance or repeated oral doses.

conditions.16–21 Very recently, UDCA has been under

INTRODUCTION
evaluation as a potential anticancer drug for the
Ursodeoxycholic acid (UDCA) has been used for several prevention of colon cancer in high-risk individuals.22–24
decades for the treatment of hepatobiliary disorders,1–3 Beneficial effects on biochemical and histological
including cholelithiasis,4 biliary dyspepsia, bile reflux markers of liver diseases have been reported for infants
gastritis.5 It is now prescribed for the treatment of and children with a variety of cholestatic disorders,
primary biliary cirrhosis,6–12 primary sclerosing cho- including biliary atresia, Byler disease, Alagille synd-
langitis13–15 and a range of other adult cholestatic rome, progressive familiar intrahepatic cholestasis,25–28
inborn errors of bile acid synthesis,29 total parenteral
Correspondence to: Dr K. D. R. Setchell, Department of Pathology, nutrition-associated liver disease30, 31 and cystic
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229,
USA. fibrosis-associated liver disease32–37 treated with oral
E-mail: [email protected] UDCA. However, chronic treatment of infants and

2005 Blackwell Publishing Ltd 709

710 K. D. R. SETCHELL et al.

young children is especially difficult because the thera- taking oral contraceptives, or were pregnant or
peutic forms of UDCA available have since their lactating, were excluded from enrolment.
introduction been exclusively of either capsule, or tablet
formulations.38–41 Parents of infants and very young
Study design
children with liver disease generally have to devise
ingenious means of administering UDCA after unpack- The study was an open-label randomized crossover
ing the capsules or crushing the tablets to disguise the design. Prescreening of subjects was performed
extreme bitter taste of this bile acid. This is usually 7–30 days prior to entry, and baseline evaluations
achieved with variable outcomes by mixing the powder were performed on days )2 and )1, before treatment
with flavoured liquids or foods. In many instances it still with drug. Each subject was given orally 750 mg UDCA
proves difficult to administer complete doses and daily (equivalent to 10–15 mg/kg body weight/day) in
compliance is often compromised. In order to overcome a single bolus dose as either a suspension (Ursofalk
these limitations a new oral liquid formulation of UDCA suspension, 15 mL of a 50 mg/mL concentration), or as
(Ursofalk suspension) with significant masking of the 3 · 250-mg capsules with a small amount of water for
bitterness of UDCA was recently developed as an 13 days according to a randomization schedule. After a
alternative to the presently prescribed solid formula- 14-day washout period to ensure plasma and biliary
tions. This new formulation is mainly targeted for UDCA levels returned to baseline values, the procedure
infants and young children but may also offer an was repeated in each adult with a reversal of the
alternative for adult patients who have difficulty in formulations. Because of the fact that the physical
swallowing capsules or tablets. Regulatory approval of appearance of the two formulations was markedly
any new drug formulation, however, requires demon- different it was impossible to blind the treatment
stration of bioequivalence to existing approved formu- regimens to the patient. However, all of the analytical
lations. The object of this study was to compare the determinations were performed blinded to the analyst.
pharmacokinetics and determine the extent of bioequiv- Subjects were studied as in-patients during the period
alence of this new liquid formulation (Ursofalk suspen- that samples were collected. For determination of biliary
sion) against an approved reference solid formulation UDCA enrichment, duodenal bile was obtained in the
(Ursofalk 250-mg capsules) that has been in clinical use morning using a special string device (Enterotest) that
for more than two decades for the treatment of liver was swallowed, positioned in the duodenum, and then
disease. intramuscular ceruleine was used to induce gall-bladder
contraction.42 The bile-stained string was then removed
and bile was extracted by soaking the string in 80%
SUBJECTS AND METHODS methanol. This procedure was performed 1 day before
administration of UDCA (baseline sample), and again at
Study subjects
the end of the treatment period (day 14). For determin-
Healthy adults in the age range 18–55 years and ation of UDCA pharmacokinetics, blood samples (12 mL
with normal body weight (body mass index, each) were collected into heparinized tubes through an
BMI < 25) were enrolled in the study. The study indwelling catheter placed in the anticubital vein. This
group comprised 11 females and 13 males. The study was performed on first day of the respective treatments
protocol was approved by the Human Investigations and blood draws were taken at baseline and at 0.5, 1,
Ethical Committee in Montegrotto, Terme, Italy, and 1.5, 2, 4, 8, 12 and 24 h after oral administration of
written informed consent was obtained from each UDCA. The blood was centrifuged at 3000 rpm for
subject. For inclusion in the study each subject had to 15 min and the plasma removed and frozen at )20 C
be in good health and free of acute or chronic until later analysis. On the days of admission the
diseases as indicated by medical history, physical subjects were given a standard diet consisting of a total
examination, electrocardiogram (ECG) and laboratory daily calorie intake of 2200 kcal with 30% of calories
screening tests. Subjects taking any over-the-counter derived from fat. The meals were served at approxi-
(OTC) medication within 1 week of the study, antibi- mately 12.30 pm and 7 pm each day.
otics in the prior 2 months, had a history of alcohol In addition to detailed bile acid analysis, the following
or drug abuse, undergone a cholecystectomy, were routine serum biochemistries were performed; serum

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 PHARMACOKINETICS OF URSODEOXYCHOLATE SUSPENSION 711

aspartate aminotransferase (AST), alanine aminotransf- roxy- and trihydroxy-5b-cholanaoates and their respect-
erase (ALT), gamma-glutamyltransferase (c-GT), alka- ive deuterated analogues used as internal standards.48
line phosphatase (ALP), total bilirubin, total cholesterol, GC-MS was performed on an Autospec Q mass spectro-
creatinine, blood urea nitrogen (BUN), uric acid, meter (Waters Inc., Franklin, MA) using electron
glucose, sodium, potassium, calcium, total and serum ionization (70 eV). Confirmation of the identity of each
protein electrophoresis. Haematological measurements bile acid was established from the GC retention index of
included haemoglobin, blood count and prothrombin the specific ions corresponding to UDCA and other
time. primary and secondary bile acids when compared with
authentic standards. Bile acids were quantified by
comparing the peak area of each bile acid to that of
Tolerability and compliance
the corresponding internal standards and interpolating
Each subject completed a questionnaire regarding this ratio relative to a set of calibration standards of
adverse events or symptoms at the end of each known concentrations of bile acids. The individual and
treatment and a complete physical examination was total plasma bile acid concentrations were expressed in
performed on completion of the study. Compliance was lm and the relative content of each bile acid was
assessed from measuring the number of capsules and expressed as percentage of the total bile acid content.
volume of suspension consumed by the end of the study The intra-assay precision of the method for the individ-
and from the plasma and biliary UDCA levels. ual bile acids as measured from repeat analysis of the
same sample was <6% (coefficient of variation, CV). The
intra-assay precision of the method measured as CV for
Sample bile acid analysis
UDCA was <5%, while the inter-assay CV was 11.8%.
Analysis of plasma and duodenal bile for UDCA and other
major bile acids was carried out using established and
UDCA enrichment in duodenal bile measured by HPLC
validated methodologies based on stable-isotope dilution
gas chromatography–mass spectrometry with selected The relative proportion of UDCA and the principal
ion monitoring (GC-MS-SIM) and by reverse-phase primary and secondary bile acid conjugates in the
high-performance liquid chromatography (HPLC).43 Enterotest samples of duodenal bile was determined by
reverse-phase HPLC essentially as described by Rossi
et al.49 The stained Enterotest strings were soaked and
Measurement of plasma bile acid concentrations by
sonicated in 10 mL of methanol to solubilize bile acids42
GC-MS-SIM
for subsequent analysis by HPLC. The methanolic extract
Bile acids were quantitatively extracted from plasma by was reduced in volume by evaporation under a stream of
solid-phase extraction on small Bond-Elut C18 car- nitrogen and reconstituted in the HPLC mobile phase
tridges44, 45 after addition of deuterated internal stand- (100–500 lL). In cases where there was inadequate bile
ards, [2,2,4,4-2H4]ursodeoxycholic, [2,2,4,4-2H4]cholic staining of the Enterotest strings (string failures), UDCA
acid, [2,2,4,4-2H4]deoxycholic, [11,12-2H2]chenode- was measured by the more sensitive GC-MS method
oxycholic and [11,12-2H2]lithocholic and as described exactly as described above for the plasma samples.
in detail previously.46 Extracted bile acid conjugates Reverse-phase HPLC was performed using a Thermo-
were then subjected to solvolysis and enzymic hydroly- separation Spectrasystem HPLC system equipped with a
sis. After hydrolysis, unconjugated bile acids were 25 · 0.46 cm Hypersil 5 lm ODS column. Chromato-
extracted on a Bond-Elut C18 cartridge and recovered graphic separation of bile acid conjugates was achieved
by elution with methanol. Bile acids were then isolated using a mobile phase of methanol and 0.01 m KH2PO4
and separated from neutral steroids by lipophilic anion- (75:25, v/v), adjusted to pH 5.3 and flow rate of
exchange chromatography47 and converted to volatile 1.5 mL/min, and bile acids were detected by UV
methyl ester-trimethylsilyl (Me-TMS) ether derivatives. absorption at 205 nm.
The Me-TMS ethers were analysed by GC-MS with SIM of The UDCA content was expressed as percentage of
the specific ions m/z 383, m/z 370, m/z 372 and m/z total bile acids by calculating the sum of chromato-
374 corresponding to specific electron ionization graphic area for UDCA conjugated as a proportion of the
(70 eV) fragments derived from monohydroxy-, dihyd- total area of bile acids. All individual bile acid curves

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712 K. D. R. SETCHELL et al.

had r-values of ‡0.99. The interassay CV was 5% product) is deemed under regulatory standards to be
for tauroursdeoxycholic acid (TUDCA) and 6.2% for necessary to establish equivalence between any two
glycoursodeoxycholic acid (GUDCA) for a mixture of drugs.
standard bile acids and 14.6% for TUDCA and 7% for Assuming a 90% power, a one-sided significance level
GUDCA when an Enterotest extract was used as quality of 5%, and an analytical standard deviation of 8% for
control. The detection limit of the method was 5 lg/mL measurement of UDCA enrichment in bile, 17 patients
(0.01 mm). were needed to assess bioequivalence between the test
and the reference formulation. Taking into account a
possible 30% failure rate of the Enterotest method used
Assessment of drug bioequivalence
to collect duodenal bile, a total of 24 patients were
Bioequivalence was based upon comparisons of the subsequently enrolled in the study.
plasma UDCA concentrations after single bolus oral The primary variables and HI were analysed by anova.
administration and on the relative percentage biliary The statistical model tested the effects of drug treatment
UDCA enrichment after daily administration of both sequence, subjects and treatments. In addition, this
formulations for 14 days. The pharmacokinetics was model tested the two one-sided hypotheses at a 0.05
determined from the appearance/disappearance profiles level of significance, by constructing the 90% confid-
for plasma UDCA concentrations. The extent of bio- ence interval (CI) for the estimate of the ratio between
equivalence of the two formulations was determined the geometric mean values of biliary enrichment of
from measures of the apparent bioavailability assessed UDCA, AUCt, Cmax assuming logarithmic distribution.
from the area under the plasma UDCA concentration– For Tmax, a normal distribution was assumed to
time curve (AUC0)12h), and from the maximum plasma construct the 90% CI for the difference between the
concentration (Cmax), and time taken to attain maxi- expected arithmetic mean values. The test (Ursofalk
mum plasma concentration (Tmax). The AUC up to the suspension) and the reference formulation were to be
12 and 24 h measured time-points (AUC0)12h and considered as equivalent if the 95% CI of the ratio of
AUC0)24h) was calculated by conventional linear tra- geometric mean values of biliary enrichment in UDCA
pezoidal rule. and the AUCt and Cmax, lay between a range of 0.80
Biliary enrichment of UDCA at the end of each 14-day and 1.25.
treatment period was expressed as the relative percentage
of UDCA (GUDCA + TUDCA) to the total biliary bile acid
concentration. This pharmacokinetic parameter is a RESULTS
measure of how much UDCA reaches the target organ
Compliance
under steady-state conditions. Secondary measures that
were compared, included the change in the biliary bile All study subjects successfully completed the treatment
acid composition [chenodeoxycholic acid (CDCA), cholic periods with no significant deviation from the protocol.
acid (CA), deoxycholic acid (DCA), lithocholic acid (LCA)] The tolerability of both formulations was found to be
and change in hydrophobicity index (HI) of duodenal bile excellent and there were no reports of adverse events
between baseline and postadministration of each formu- during the study. Based upon the amounts of study drug
lation. Bile acid HI was calculated according to Heuman’s returned after each treatment period, compliance was
formula50 as follows: HI ¼ E · HIx · Fx where, HI is the confirmed. The expected number of capsules and
individual HI for the glyco- or tauro-conjugate of each bile volumes of liquid were taken by each subject. Compli-
acid and Fx is the proportion of the individual bile acids in ance was further indicated from measurements of the
the duodenal bile. plasma UDCA concentration that in all subjects was
significantly elevated above normal during treatment.
Statistical analysis
Biliary enrichment
Biliary enrichment in UDCA was taken as the primary
end-point for estimation of the appropriate sample size. The extent of bile staining of the terminal portion of the
A maximum allowed difference of 8% in UDCA biliary string was variable among subjects irrespective of the
enrichment (i.e. ±20% difference from the reference drug treatment, but adequate amounts of duodenal bile

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 709–721

 PHARMACOKINETICS OF URSODEOXYCHOLATE SUSPENSION 713

were obtained for HPLC analysis in all but five subjects. (0.8–1.25). Thus, the two formulations were found to
In these five string failures concentrations of biliary bile be identical in bioequivalence with regard to biliary
acids were too low for quantification by HPLC and these UDCA enrichment achieved under steady-state condi-
were subsequently measured by GC-MS. The mean tions (Table 1).
(±s.d.) biliary enrichment of UDCA before and after
administration of test and reference formulations is
Pharmacokinetics
shown in Figure 1.
There was no significant difference in the baseline The mean UDCA plasma concentration–time curves for
biliary UDCA level which was expectedly low and in the both formulations are shown in Figure 2. The profiles of
physiological reported range when expressed as a the plasma appearance/disappearance curves were
percentage of the total biliary bile acids measured.1, 2 similar and characterized by a rapid increase in UDCA
Geometric mean values and the ratio for test/reference in plasma followed by a slower elimination phase. The
formulation for UDCA enrichment are shown in time to attain maximal plasma UDCA concentration
Table 1. The 95% CI for the ratio of geometric mean (Tmax) was 3.56 h for Ursofalk suspension when
values of Ursofalk suspension and Ursofalk capsules was compared with 2.56 h for Ursofalk 250-mg capsules,
within the accepted standard bioequivalence range and this difference was not statistically significant
(Table 1). The absorption and elimination rates followed
first-order kinetics, and pharmacokinetic measures were
computed based on this model. The mean peak plasma
concentration (Cmax) and bioavailability as measured
from the AUC0)12h of the suspension and the reference
capsules were comparable and within the range of
equivalence. These data are summarized in Table 1.

Pharmacodynamic effects of UDCA administration

There was a significant decrease in the HI of duo-
denal bile following administration of the suspension
(Table 1). Mean (±S.E.M.) values decreased from
0.31 ± 0.08 in the pre-treatment bile to 0.014 ±
0.028 (P < 0.05) after administration of the UDCA
suspension, and correspondingly from 0.33 ± 0.06 at
Figure 1. Arithmetic mean (±s.d.) biliary ursodeoxycholic acid
(UDCA) enrichment after 14 days administration of 750 mg/day baseline to )0.033 ± 0.018 (P < 0.05) for the UDCA
dose of UDCA given as Ursofalk capsules (reference) or as Ursofalk capsules (Figure 3). The HI was decreased by 95%
suspension (test formulation). during administration of suspension and 106% during

Table 1. Plasma pharmacokinetics after single dose administration of 750 mg ursodeoxycholic acid (UDCA) in the form of an Ursofalk
suspension (T) or as Ursofalk 250-mg capsules (R) and biliary UDCA enrichment and hydrophobicity index (HI) after a 14 days
administration of 750 mg UDCA/day

Parameters Suspension (T) Capsules (R) Ratio (T/R) 95% CI for T/R

Biliary enrichment (%)* 45.1 ± 1.0 47.9 ± 1.0 0.94 0.85–1.04

AUC0)12h (lmol h/L)* 150.5 ± 1.0 134.5 ± 1.0 1.12 1.01–1.24
Cmax (lm)* 22.7 ± 1.0 22.7 ± 1.0 1.00 0.81–1.24

Difference (T ) R) 95% CI for T ) R

Tmax (h)  3.56 ± 0.51 2.56 ± 0.51 1 )0.49 to 2.49
HI  0.014 ± 0.028 )0.033 ± 0.018 )0.05 )0.034 to 0.127

Values expressed as means ± S.E.M.

* Geometric mean.
  Arithmetic mean.

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714 K. D. R. SETCHELL et al.

significantly different between the two formulations

(6.51 ± 2.1 vs. 3.77 ± 3.04, mean ± s.d. for suspen-
sion vs. capsule).

DISCUSSION

The present study was designed to evaluate the

bioequivalence of a new liquid formulation of UDCA
(Ursofalk suspension) with that of a conventional
approved solid capsule in healthy volunteers at the
usual therapeutic doses of 10–15 mg/kg body weight/
day currently recommended for solid forms of UDCA in
Figure 2. Plasma ursodeoxycholic acid (UDCA) concentration
the treatment of hepatobiliary disease. The new liquid
(lm, mean ± s.d.) profiles following single bolus oral administra-
tion of 750 mg Ursofalk suspension, or 750 mg Ursofalk capsules formulation was developed with the aim of achieving
to the same healthy adults. the same UDCA release profile to a currently prescribed
reference formulation, Ursofalk 250-mg capsules. UDCA
is poorly soluble in water1, 2 and therefore, to achieve a
liquid formulation, an excipient was used to produce
a suspension. To mask the natural bitter taste of UDCA,
a sweetener was added. The widespread availability of a
liquid formulation is needed to facilitate compliance to
UDCA therapy particularly in infants and children with
cholestatic liver disease that presently have to be given
by the parents the powdered contents of commercial
UDCA capsules or tablets disguised in some form of food
sweetener. From a practical perspective, presently it is
also difficult to titrate accurate doses of UDCA in the
young patients. Based on the therapeutic dose range
Figure 3. Change in hydrophobicity index (HI, mean ± S.E.M.) of (10–15 mg/kg body weight/day) an infant of 5–10 kg
duodenal bile after oral administration for 14 days of ursodeoxy- body weight should be prescribed 50–150 mg/day,
cholic acid (UDCA) (750 mg/day) given as Ursofalk capsules
however, currently approved capsules are marketed as
(reference) or as Ursofalk suspension (test formulation).
250 mg or 300 mg doses. Commercial availability of a
liquid formulation of UDCA would make it possible to
administration of the reference UDCA capsules, and deliver the exact prescribed dose according to the body
there was no statistically significant difference between weight of the infant. Furthermore, this formulation
the two different formulations of UDCA. could also be useful for adults who find it difficult to
Following both formulations, there was a significant swallow capsules.
change in the composition of the biliary bile acid pool. Changes in a drug formulation may alter in vitro
There occurred a decrease in the proportion of biliary dissolution or gastrointestinal absorption,51 and hence
CA, from 37 to 18% during administration of the affect bioavailability, and therefore it is necessary to
suspension and from 35 to 21% when the capsules were demonstrate bioavailability and bioequivalence of any
given. The proportion of CDCA similarly declined from new formulation for approval to be granted by Drug
39% at baseline to 24% for suspension, and from 38 to Regulatory Agencies. In vitro comparative dissolution
21% for capsules. A decrease in the relative proportion studies have shown that Ursofalk suspension and
of DCA was observed after both formulations, but LCA, Ursofalk capsules have equivalent release profiles
which accounted for a relatively small proportion of the (manufacturer’s proprietary data – unpublished), and
total biliary bile acids (<1.5%), did not change after this is supported by the clinical data presented here.
administration of either bile acid formulation. The ratio Bioequivalence was assessed under two different
of glycine-/taurine-conjugated biliary bile acids was not conditions. Classical single bolus oral pharmacokinetics

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 709–721

 PHARMACOKINETICS OF URSODEOXYCHOLATE SUSPENSION 715

of the two formulations was carried out to determine absorption and plasma characteristics to an existing
bioavailability and to compute pharmacokinetic char- approved formulation. Plasma concentrations levels
acteristics of the drug from the plasma appearance/ after single administration of UDCA are especially useful
disappearance profiles of UDCA. Then, under steady- for the in vivo evaluation of new formulations with
state conditions of chronic (repeated) dosing for a period modified release (delayed, multiple release, etc.) because
of 2 weeks, the concentration of the UDCA at the site of they predict the rate and extent of intestinal absorption.
action, in this case the liver was compared from the However, they are less informative in determining how
UDCA enrichment in duodenal bile samples. much of the drug reaches the target tissue. In the case
The results of this study established that this new of UDCA, the target organ is the liver and gall-bladder,
liquid formulation of UDCA is equivalent to standard and therefore measures of plasma bile acid concentra-
Ursofalk capsules currently in clinical use with respect tions are not so informative of whether the drug is
to plasma UDCA pharmacokinetics and biliary UDCA reaching its target. Circulating bile acid concentration
enrichment. UDCA absorption and ‘apparent bioavail- reflects the balance between intestinal input and hepatic
ability’ determined plasma UDCA pharmacokinetic extraction and in health the latter is efficient leading to
parameters were similar following single dose adminis- relatively low plasma bile acid concentrations.56 Also,
tration of the suspension and the capsules (Table 1). intestinal absorption of UDCA can be affected by the
The plasma concentration appearance/disappearance formulation and co-administration of other agents.57–59
curves of both formulations were similar and charac- When UDCA is administered, plasma UDCA concentra-
terized by rapid appearance of UDCA in plasma with tions are usually very low and poorly correlate with the
peak concentrations occurring 2 h after oral adminis- amount the bile acid that reaches the site of action, the
tration followed by a slower terminal elimination phase. liver.60 Biliary enrichment is crucial to achieving
This is consistent with other pharmacokinetic studies of efficacy. It is biliary UDCA enrichment and not plasma
UDCA,38–41, 52 where in most cases the peak UDCA UDCA concentration that best correlates with decrease
concentrations are observed between 2 and 4 h after in total bilirubin and Mayo risk score in patients with
oral administration. Delayed absorption, with peak primary biliary cirrhosis.60 In addition, the increase in
plasma UDCA concentrations has been achieved with biliary UDCA correlates significantly with decreases in
sustained release formulations of UDCA,41, 53 although serum transaminases and alkaline phosphatase.33, 61, 62
it was shown such formulations made no significant In this bioequivalence study, we determined the biliary
difference to the biliary UDCA enrichment.41 The UDCA enrichment under steady-state conditions and
AUC0)12h was calculated from the plasma UDCA this differs from previous pharmacokinetic studies of
concentrations for the time-points 0–12 h only in order UDCA where bioavailability has been assessed only after
to minimize effects due to enterohepatic recycling of a single dose oral administration using the plasma
UDCA where otherwise a second peak plasma concen- kinetics.38–41, 53, 63 Our study was conducted in healthy
tration is often observed.54, 55 However, similar results subjects using a dose of 750 mg given once daily. The
were obtained when AUC0)24h was computed for decision to perform these studies in healthy volunteers,
the two formulations. These plasma profiles are quali- rather than patients was based on the fact that similar
tatively consistent with the findings of other investi- biliary UDCA enrichments (approximately 45%) are
gators who have compared various preparations of observed for healthy volunteers and gallstone patients
UDCA.38–41 While it is difficult to accurately compare following chronic administration of doses of 8–12 mg/
the different published studies on UDCA pharmacoki- kg body weight/day (see Table 2) and because this is a
netics because of differences in study designs and standard approach in drug evaluation. Lower biliary
analytical methods, there are considerable differences UDCA enrichments are often observed in patients with
among studies in the ‘apparent bioavailability’ of UDCA chronic cholestatic liver disease as indicated in Table 2
when the reported plasma AUC are compared on a dose- which summarizes many published studies. This lower
adjusted basis. This is perhaps not surprising when enrichment in liver disease is mainly explained by
significant differences in the in vitro dissolution rates for impaired hepatic bile acid uptake and/or reduced
different UDCA preparations have been demonstrated.51 canalicular bile acid secretion,2 although severe chol-
For most drugs bioequivalence is based upon demon- estasis can impair intestinal absorption of UDCA,64 as
strating that a new formulation exhibits the same does the use of bile acid-binding agents.57, 58

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 709–721

 Table 2. Published studies comparing the extent of biliary UDCA enrichment expressed as a percentage of the total biliary bile acids
716

Study reference Study subjects (N) UDCA preparation Dose Biliary UDCA (%)

Healthy subjects
Federowski et al.68 Healthy volunteers (n ¼ 7) UDCA, Tokyo Tanabe, Japan 1000 mg/day 56 ± 7
Batta et al.69 Healthy volunteers (n ¼ 4) Actigall 300 mg capsules, Ciba-Geigy, USA 900 mg/day 55 ± 7
Galzigna et al.70 Healthy volunteers (n ¼ 24) Ursofalk 250-mg capsules, Germany 750 mg/day 47 ± 10
Galzigna et al.71 Healthy volunteers (n ¼ 24) Ursofalk suspension 750 mg/day 44 ± 11
Galzigna et al.71 Healthy volunteers (n ¼ 24) Ursofalk 150/300 mg capsules, Italy 750 mg/day 43 ± 9
Biliary disease patients
Makino and Nakagawa72 Gallstone patients (n ¼ 23) UDCA, Tokyo Tanabe, Japan 150 mg/day 28 ± 8
600 mg/day 53 ± 8
K. D. R. SETCHELL et al.

Roda et al.73 Gallstone patients (n ¼ 7) UDCA 125 mg capsules, Guliani, Italy 12 mg/kg body weight/day Approximately
55
Salen et al.74 Gallstone patients (n ¼ 21) UDCA 250 mg capsules, Tokyo Tanabe, Japan 250 mg/day 29 ± 3
1000 mg/day 51 ± 6
Ponz de Leon et al.75 Gallstone patients (n ¼ 11) UDCA capsules, Giuliani, Italy 15 mg/kg body weight/day 42 ± 17
Carulli et al.76 Gallstone patients (n ¼ 25) UDCA, Gipharmex, Italy 15 mg/kg body weight/day 54 ± 5
Stiehl et al.77 Gallstone patients (n ¼ 10) Ursofalk 250-mg capsules, Germany 12–16 mg/kg body weight/day 64 ± 2
Bateson et al.78 Gallstone patients (n ¼ 24) UDCA, Tokyo Tanabe, Japan 250 mg/day 26 ± 2
500 mg/day 35 ± 3
750 mg/day 50 ± 3
1000 mg/day 50 ± 5
Thistle et al.66 Gallstone patients (n ¼ 6) UDCA, Tokyo Tanabe, Japan 5.8 mg/kg body weight/day 40
10.6 mg/kg body weight/day 49
Ward et al.5 Gallstone patients (n ¼ not stated) Various formulations 150 mg/day 19–29
250–300 mg/day 26
450–500 mg/day 29–35
600–750 mg/day 42–53
>750 mg/day 50–64
von Bergmann et al.79 Gallstone patients (n ¼ 10) Ursofalk 250-mg capsules, Germany 1000 mg/day 43
Stiehl et al.80 Gallstone patients (n ¼ 5) Ursofalk 250-mg capsules, Germany 250 mg/day 29 ± 2
500 mg/day 41 ± 3
750 mg/day 46 ± 3
1000 mg/day 53 ± 2
1250 mg/day 53 ± 2
Bazzoli et al.81 Gallstone patients (n ¼ 39) Not known 400 mg/day 31 ± 3
Frenkiel et al.82 Gallstone patients (n ¼ 55) UDCA, Gipharmex, Italy 750 mg/day 53 ± 1
Zuin et al.83 Gallstone patients (n ¼ 12) UDCA 250 mg capsules, Italy 15 mg/kg body weight/day 55 ± 6
Fischer et al.84 Gallstone patients (n ¼ 7) Ursofalk 250-mg capsules, Germany 750 mg/day 43 ± 17
Miettinen et al.85 Gallstone patients (n ¼ 7) Adursal, Leiras 23–25 mg/kg body weight/day 62 ± 4
Shiffman et al.86 Gallstone patients (n ¼ 32) Actigall 300 mg capsules, Ciba-Geigy, USA 300 mg/day 14 ± 11
600 mg/day 21 ± 14
1200 mg/day 34 ± 22

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 Liver diseases
Podda et al.87 Chronic active hepatitis (n ¼ 18) UDCA 250 mg, Italy? 250 mg/day 22
500 mg/day 32
750 mg/day 34
Podda et al.87 PBC (n ¼ 18) UDCA 250 mg, Italy? 250 mg/day 25
500 mg/day 31
750 mg/day 37
Roda et al.88 PBC (n ¼ 7) UDCA, Italy? 600 mg/day 34 ± 1
Podda et al.16 Chronic active hepatitis (n ¼ 24) UDCA, Italy? 600 mg/day 31
Colombo et al.32 CF-liver disease (n ¼ 9) UDCA, Italy? 10–15 mg/kg body weight/day 25 ± 7
Nakagawa et al.89 CF-liver disease (n ¼ 5) UDCA, Italy? 10–15 mg/kg body weight/day 12–33
Crossignani et al.90 BRIC (n ¼ 1) UDCA, Italy? 750 mg/kg body weight/day 35
Mazzella et al.91 PBC (stages I–III; n ¼ 9) UDCA 300 mg, Italy? 600 mg/day 34 ± 1
Crosignani et al.92 PBC (n ¼ 10) UDCA, Italy? 500 mg/day 33 ± 1
Crosignani et al.93 Chronic active hepatitis (n ¼ 18) UDCA 250 mg, Italy? 250 mg/day 22 ± 1
500 mg/day 32 ± 3
750 mg/day 34 ± 2
Batta et al.69 PBC (n ¼ 14) Actigall 300 mg capsules, Ciba-Geigy, USA 900 mg/day 31 ± 12
Lindor et al.8 PBC (n ¼ 89) Ursofalk 250-mg capsules, Germany 13–15 mg/kg body weight/day 40
Combes et al.94 PBC (stages I–II; n ¼ 28) Actigall 300 mg capsules, Ciba-Geigy, USA 10–12 mg/kg body weight/day 37 ± 12
PBC (stages III–IV; n ¼ 49) 42 ± 17
PBC (stages I–IV; n ¼ 77) 43 ± 13

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Stiehl et al.14 PSC (n ¼ 10) Ursofalk 250-mg capsules, Germany 750 mg/day 31 ± 3
van de Meeberg et al.61 PBC (n ¼ 19) and PSC (n ¼ 8) Ursofalk 250-mg capsules, Germany 10 mg/kg body weight/day 41 ± 3
Fracchia et al.95 PBC (n ¼ 6), PSC (n ¼ 1) Not stated 600 mg/day 54 ± 12
Invernizzi et al.96 PBC (n ¼ 12) UDCA, Pharmacia, Italy 750 mg/day 29 ± 6
Combes et al.11 PBC (n ¼ 54) UDCA, Actigall 300 mg capsules, Ciba-Geigy, USA 10–12 mg/kg body weight/day 40 ± 16
Other conditions
Nilsell et al.97 Hyperlipdaemia (n ¼ 12) UDCA 125 mg capsules, Tokyo Tanabe, Japan 15 mg/kg body weight/day 50 ± 4
Angelin et al.98 Hyperlipidaemia (n ¼ 5) UDCA, Tokyo Tanabe, Japan 7.5 mg/kg body weight/day 46 ± 9
15 mg/kg body weight/day 50 ± 4
Mazella et al.99 Obesity–weight management (n ¼ 10) UDCA 150 mg capsules, Gipharmex, Italy 10 mg/kg body weight/day 45 ± 1
Mazella et al.99 Obesity–weight reduction (n ¼ 10) UDCA 150 mg capsules, Gipharmex, Italy 10 mg/kg body weight/day 49 ± 1

PBC, primary biliary cirrhosis; BRIC, benign recurrent intrahepatic cholestasis; PSC, primary sclerosing cholangitis; CF, cystic fibrosis; UDCA, ursodeoxycholic acid.
PHARMACOKINETICS OF URSODEOXYCHOLATE SUSPENSION
717
718 K. D. R. SETCHELL et al.

Unlike most drugs, where the site of action or target greatly facilitate the treatment of paediatric patients
tissue may be inaccessible to sampling, relatively low where solid forms of the drug are only available.
invasive procedures can be used to sample duodenal
bile. In order to reduce the discomfort of conventional
ACKNOWLEDGEMENTS
duodenal intubation, a proven alternative method of
collecting duodenal bile was used. This previously This study was supported by a grant from Dr Falk
validated procedure involved the placement of a special Pharma, Freiburg, Germany.
string (Enterotest) to sample duodenal bile.42 In most
subjects successful sampling was obtained, however,
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