EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1986, Vol. 11, No 2, pp.

145-149

Absolute bioavailability of testosterone

after oral administration
of testosterone-undecanoate and testosterone

U. TAUBER, K. SCHRODER, B. DDsTERBERG and H. MATTHES

Research Laboratories, Schering AG, Berlin (West)

Received for publication: March 19, 1986

Key-words: Testosterone, testosterone-undecanoate, absolute bioavailability, oral administration

SUMMARY

The plasma levels of testosterone (T) were measured after oral administration of 25 mg T and 40 mg testosterone-undecanoate
(TU) in a group of young women by a specific radioimmunoassay. Plasma levels were compared to those after intravenous administra-
tion of 1.5 ug testosterone/kg to another group of young women for determination of absolute bioavailability. Due to the high meta-
bolic clearance rate of 24.5 mlfminjkg absolute systemic availability of free testosterone was calculated to 3.56 ± 2.45%. Oral adminis-
tration of testosterone undecanoate leads only to an absolute testosterone bioavailability of 6.83 ± 3.32%.

INTRODUCTION SUBJECTS AND METHODS

Androgen deficiency syndromes in men are A total of 18 female volunteers participated in

commonly treated by intramuscular administration
of testosterone(T)-esters like T-propionate and/or
enanthate. Testosterone-esters are completely
released from intramuscular depots and easily
hydrolized leading to T plasma level in the desired
range up to 2-3 weeks (I, 2). Oral administration of
T seems to be inadequate for substitution therapy
since T is presystemically eliminated during the
absorption process and the first liver passage (3, 4).
Previously it has been shown that normal T levels
can be achieved in hypogonadal men by adminis-
tering high doses of TU orally (I, 5). It was the aim
of the present study to investigate the absolute
bioavailability of T after oral administration of T
and TU. The study was performed in female volun-
teers with low endogeneous T levels which did not
interfere with exogenous administered testosterone.
Send reprint requests to: Dr. Ulrich Tauber, D. Pharmac-
okinetics A, Schering AG, Miillerstrasse 170-178, D-lOOO
Berlin 65.
both studies. Subjects were shown by physical
examination to be in good health with normal hem-
atology and blood and urine biochemistry. The
nature and purpose of the study were explained
before each subject was asked to give her written
informed consent.
Study 1
6 female young volunteers (see Table I) received
1.5 ug T/kg as solution in propylene glycol water
20/80 v]» in a concentration of 20 ug/ml intraven-
ously as a short infusion over ten minutes.
Plasma T levels were measured immediately
before administration and 5, 10, 15, 20, 30, 45
minutes, I, 1.5, 2, 3, 4, 6, 8 and 24 hours after
administration with a specific commercial avail-
able radioimmunoassay (immunogen: testo-
sterone-lla-(succinyl)BSA, Steranti).
146 European Journal of Drug Metabolism and Pharmacokinetics. 1986. No 2

Table I: Biological data of volunteers.

Study 1

Subject No. 1 2 3 4 5 6

age (years) 25 24 24 21 23 20

weight (kg) 57.5 59.5 64.0 53.5 47.5 64.7

height (ern) 173 161 173 162 164 178

Study 2

Su,bjeet No. 1 2 3 4 5 6 7 8 9 10 11 12

age (years) 31 28 30 31 29 30 33 30 35 32 28 32

weight (kg) 83 67.5 56 54 50 75 55 56 57 61 56.5 66.5

height (ern) 172 178 170 162 156 156 161 160 161 167 176 180

Study 2 individual area under the testosterone

25 mg T (capsules contammg 6.25 mg T dis-
solved in paraffinoil (miglyol 810) and 40 mg TV *
( ~ 25 mg T) were administered in a random
sequence to 12 ovulating women (see Table I)
between day 3 and 7 of the cycle. The time interval
between both administrations was at least 2 days.
Plasma T levels were assayed 0.25, 0.5, I, 1.5, 2, 3,
4, 6, 8, 12 and 24 hours after administration as in
study I. Participants in the study had undergone
tubal ligation or wore an IVD.
Pharmacoklnetic evaluation
Areas under the T plasma level time curves
(AVC-values) were calculated using the trapezoidal
rule.
Total plasma clearance CL of T after intrave-
nous administration of dose D iv is given by CL =
DivlAVCiv'
Absolute bioavailability BA after oral adminis-
tration of T and TV in doses of D po results from (I)
BA (%) = 100 . Al!C po . Div
AVCiv D po
AOC iv mean area under the testosterone
plasma level curve after i.v. administra-
tion
D iv intravenous dose per kg body weight
Dpo oral dose per kg body weight
* Andriol (!) manufacturer Organon.
plasma level curve after p.o. adminis-
tration
RESULTS
Study 1
The mean plasma T concentrations above basal
levels after intravenous administration of 1.5 ug
T/kg are shown in Fig. I. Highest plasma levels
were found at the first time point 5 minutes after
the end of the short infusion with 5.40 ± 1.69 ng
Tzrnl corresponding to 16.9 ± 5.3% of the dose
administered in total plasma volume. Testosterone
plasma levels decayed with a half-life of 10.3 ± 7.9
minutes. Areas under the T plasma levels curves
were calculated to 67.5 ± 22.05 ng x min/ml (~
1.125 ± 0.368 ng x h/ml), From the quotient Divl
AVC iv the total plasma clearance of T can be esti-
mated to be 24.5 ± 8.7 ml/min/kg.
Study 2
(1)
Figures 2A and B show the mean plasma levels
of T after oral administration of 25 mg T and of 40
mg TV. A great intersubject variability has been
observed in T level curves after both administra-
tions. Following oral dosing of T highest mean
levels of approximately 4 ng Tjrnl have been mea-
sured 5 minutes after ingestion.
After administration of TV mean peak levels of
approximately 4 ng TIml have been observed 4
hours after dosing. Areas under the plasma level
 U. Tauber et al.• Absolute bioavailability of testosterone 147

'1Mtoarone plume IeYeI.tt.r Inbawenoua

edmlnlllballutt of 1.5PSI Tiki to 8 young .....18. (mun ± 80)
Y ng Testosterone/ml
8
7.
6 .
5

-\
4

~
2
1
I r
0 I
0 10 20 30 40 50 60
Minutes

Fig. 1: Testosterone plasma level after intravenous administration of 1.5 ~g T/kg to 6 young females (mean ± SD).

curves amounted to 11.7 ± 8.2 ng x h/ml after

oral T and to 20.9 ± 11.6 ng x h/ml after oral TV
administration. •
of 25 mg T (A) 8nd 40 mg 1U (8)
ng Testosterone/ml
to.
T. . . .rone pIMma level after oral8dmlnlstnltlon
women

7 A

Bioavailability 6
5
Individual absolute bioavailability data after
oral administration of 25 mg T and 40 mg TV (~
.
25 mg T) in women are given in Table II. After 3 1'1).-
ingestion of T 3.66 ± 2.45% of the dose adminis- ~I\
tered have become systemically available; receiv- 2
ing TV absolute bioavailability of T increased to
6.83 ± 3.32%. Areas under the T plasma level
curves and consequently also bioavailability
1

0
B
1\ 1./~~
showed a remarkable intersubject variation for
7
both oral treatments.
6
5
DISCUSSION .
In the case of T it has been known for a long 3
time that an oral replacement therapy of T is 2
impractical (3, 4). In recent years T substitution
therapy with high doses of TV has been introduced
but no data for absolute bioavailability have been O~..J.....I-+-~-+--'--+---'~I--L-t-..l...-+---I
published. Absolute bioavailability data presented
here have been derived from a comparison of two
o 2 .. 6 8 10 12
Hours
groups of young, healthy women. Commonly abso-
lute bioavailability studies are performed as an Fig. 2: Testosterone plasma level after oral administration
intraindividual comparison to minimize variation. of 25 mg T (A) and 40 mg TU (B) to 9 women.
148 European Journal of Drug Metabolism and Pharmacokinetics, 1986. No 2

Table II: Bioavailability (BA) and areas under the T plasma level curves (AVC) after intravenous and oral administration of testos-
terone (T) and after oral administration of testosterone-undecanoate (TV) to young women.

Study 1 Study 2
T T m
i.v. p ;o, p ,o,
1.5 ~a/ka 25 lIa/Subject 40 lIa (ll 25 11& T/subj.)
Subject No AUC BA Subject No AUC BA AUC SA
na/ll1 X h ~ ng/Ill x h ~ ng/1I1 x h %

1 0.67 1 7.3 3.23 12.8 5.67

2 1.14 2 5.7 2.05 10.1 3.64
3 1.66 3 11.0 3.28 - -
I, 1.20 4 - - 27.5 7.92
5
6
0.76
1.33
5
6
11.4
-
3.04
-
-
13.5
-
5.40
7 3.0 0.90 10.2 2.99
8 11.1 3.32 28.2 8.42
9 31.5 9.58 38.5 11.70
10 11<.6 4.75 36.1 11.74
11 9.4 2.83 - -
12 - - 11.2 3.97

_an 1.13 100 ..,an 11.7 3.66 20.9 6.83

SO 0.37 SO 8.2 2.45 11.6 3.32
. .dian 1.17 llledian 11.0 3.23 13.5 5.67
Q2S 0.74 Q2S 6.25 2.44 10.7 3.81
Q7S 1..41 Q75 13.0 4.04 32.2 10.1

no administration

Bioavailability based upon a two group compar-
ison could slightly influence the absolute figures
but not its magnitude or the relation between oral T
and TV bioavailabilities. Obviously not only T but
also TV is subject to a high presystemic elimination
in humans during the absorption process and the
first liver passage. T is rapidly metabolized in the
liver but extrahepatic biotransformation has also
been reported (6). This is reflected in a total plasma
clearance of 24.5 ± 8.7 ml/min/kg.
Due to this high metabolic clearance intraven-
ously administered T rapidly disappears from the
plasma. Only small amounts of T reach systemic
circulation after oral administration. Very high
doses of oral T are necessary to reach physiological
plasma levels (4). Metabolic clearance rate of Tin
men is even higher than in women (7). Clearance
rates after steady state infusion of radio-labelled T
of 675 ± 1391/day in women and of 1288 ± 221 If
day in men have been reported (8). These clearance
rates are less than that of the present study because
they represent clearance of labelled substances in
plasma (testosterone and metabolites), but indicate
a nearly 2-fold higher clearance for men. Therefore
it has to be expected that absolute bioavailability of
orally administered T in men is still lower than in
women.
This assumption was confirmed by measuring a
mean incremental rise of T plasma level areas of
about 35 nmolfl x h( ~ lOng x h/ml) after inges-
tion of 100 mg T in fasted male volunteers and of
50 nmolfl x h (~ 14.4 ngjml x h) in the same
volunteers when 100 mg T were taken together with
a breakfast containing 59% fat (9). Dose corrected
AVC-values in man based on equivalent doses ofT
were approximately 4-fold less than AVC-values in
women.
After oral administration of 100 mg TV to
hypogonadal men transient T plasma levels in the
desired range of 7 ng/ml (~ 25 nmolfl) have been
measured but also a great variabiliy in levels and
areas between subjects has been observed (5, 9, 10).
Cantrill et al. 1984 (1) report peak concentrations
of T between 11.5-60.1 nmolfl (~ 3.3-17.3 ng/ml)
and AVC-values ranging from 67.0-276.0 nmol/l x
h (~ 19.3-79.6 ng x h/ml) after twice daily oral
administration of 80 mg TV to 6 hypogonadal men.
If TV was not taken together with a very fat break-
fast T bioavailability was not greater than that of
micronized T. TV administered as tablet was even
less available as compared to T (9).
The normal endogenous production rate of T
which has to be replaced therapeutically in cas-
trates and hypogonadal man is about 7 mg per day
(11). The recommended very high daily replace-
ment dose of 120-140 mg TV leads to a bioavail-
able T dose of 5-7 mg if an absolute bioavailability
of 6.8% in man is assumed. The late incidence of
maximum T levels (4 hours p.adm.) are in good
agreement with published data and may indicate
 U. Tauber et al., Absolute bioavailability of testosterone
the proposed lymphatic intestinal absorption of a
part of TV (12). Since the intestinal lymphatic flow
is very small in comparison to intestinal blood flow
the capacity of lymphatic absorption is very
limited. 2% of the dose administered have been
absorbed via the lymphatic system within 5 hours
in the rat (12). It has to be taken into account that
the bulk of TV is absorbed via the portal vein and
more than 90% of the dose are inactivated during
the first liver passage without reaching systemic cir-
culation. This represents a large steroid load to the
liver with possible long term effects which have not
been studied (1, 9). Additionally the high degree of
variability seen in plasma levels and bioavailability
may represent the reason for reported unsatisfac-
tory clinical response (1).
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