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Reduction by Finasteride or Dutasteride and Food Intake in Men
From the Center for Research in Reproduction and Contraception, Divisions of General Internal Medicine and Endocrinology, Metabolism and Nutrition, Department of Medicine, University of Washington Medical School, Seattle, Washington.
| Correspondence to: Dr John K. Amory, University of Washington, Box 356429, 1959 NE Pacific St, Seattle, WA 98195 (e-mail: jamory{at}u.washington.edu). |
| Received for publication March 17, 2005; accepted for publication August 2, 2005. |
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Abstract |
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reductase inhibitor dutasteride (D), elevates serum T in
medically castrated men to the normal range. In this study, we sought to
determine the impact of 1) finasteride (F) and 2) food intake on the serum T
and dihydrotestosterone (DHT) levels observed after the oral administration of
T in oil. Therefore, we conducted a pharmacokinetic study of oral T in oil,
alone or with D or F, in the fasting and fed states in normal men whose
endogenous T production was suppressed by the GnRH antagonist acyline. After
acyline administration, 7 healthy men (mean age 31 ± 8 years) were
sequentially administered five 400-mg doses of oral T in sesame oil once
daily. The first dose of oral T (T-alone) in oil was given while fasting
without F or D. The second (fasting) and third (fed) doses were administered
after pretreatment with F (T + F). Four days later, the fourth (fasting) and
fifth (fed) doses were administered after pretreatment with D (T + D). Blood
samples for measurement of serum T and DHT were obtained before T dosing and
0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after each administration. In the
fasting state, 24-hour area-under-the-curve of serum T after oral T
administration was significantly greater with coadministration of either D or
F compared with T-alone (126 ± 36 nmol-h/L [T-alone] vs 287 ± 98
nmol-h/L [T + F] vs 236 ± 82 nmol-h/L [T + D]; P < .05 for T + F and
T + D vs T-alone). Administration of the T with food nonsignificantly
decreased serum T levels compared with fasting administration. The
administration of oral T in oil combined with either F or D results in serum T
levels adequate to treat men with testicular failure. Additional studies of
the combination of oral T in oil with 5-reductase inhibitors as a novel
form of oral T therapy are warranted.
Key words: Androgen, hypogonadism, metabolism, acyline
There is currently no safe (ie, nonalkylated) form of oral androgen therapy approved for use in the United States. Testosterone undecanoate (TU) is a long-chain testosterone ester that is used clinically in many countries for the treatment of T deficiency and is administered orally in oil. TU has been shown to be absorbed via intestinal lymphatics, bypassing the liver and reaching the systemic circulation via the thoracic duct (Coert et al, 1975; Horst et al, 1976; Shackleford et al, 2003). When dosed 3 times daily, oral TU therapy results in therapeutic increases in serum T; however, it also results in elevations in serum dihydrotestosterone (DHT) that greatly exceed the normal range (Fanchi et al, 1978; Skakkebaek et al, 1981; Gooren 1994; Houwing et al, 2003). Because of the marked increases in serum DHT seen with oral TU, concern exists about the potential for harm to the prostate associated with long-term oral TU therapy, although no increase in prostate disease has been reported to date despite long-term use of oral TU (Gooren, 1994).
Oral administration of unmodified T in a crystalline form does not result
in elevations in serum T levels due to extensive hepatic first-pass metabolism
(Foss 1939;
Johnsen et al, 1974;
Nieschlag et al, 1975;
Daggett et al, 1978). However,
we have recently reported that, when unmodified testosterone is administered
orally in sesame oil, serum T levels within the normal range can be achieved
in medically castrated normal men. Furthermore, when the oral T in oil is
combined with the 5 reductase inhibitor dutasteride, the resulting
serum T levels are roughly doubled, and serum T remains within the normal
range for 12 hours (Amory and Bremner,
2005).
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A second issue relating to oral T therapy is the role of food in absorption of an oral dose of T. The absorption of oral TU is dramatically enhanced by concomitant fat intake due to its marked lipophilicity (Frey et al, 1979; Bagchus et al, 2003). Therefore, to determine the impact of food intake and finasteride on the absorption of oral T, we conducted a pharmacokinetic study of oral T in oil. We administered T in oil alone in the fasting state, and with concomitant D or F in the fasting and fed states in normal men whose endogenous T production had been temporarily suppressed by the GnRH antagonist acyline.
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Materials and Methods |
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Study Drug
The oral T in sesame oil was prepared by the compounding pharmacy at the
University of Washington. Micronized T (U.S.P. grade, Spectrum Quality
Projects, Gardena, Calif) was added at 100 mg/mL to sesame oil (N.F. grade,
Spectrum Quality Projects) and mixed thoroughly on a magnetic stir plate to
create a homogenous T/sesame oil emulsion. The compounding pharmacist then
drew up 4 cm3 (400 mg) of the emulsion into syringes immediately
before dosing. The syringe was then sent to the Clinical Research Unit, where
it was administered to the subject.
Study Design
The study design is summarized in Figure
1. The drug-exposure period lasted 11 days. On day 0, subjects
received a single injection of the GnRH antagonist acyline (300 µg/kg SQ),
which has been shown to suppress T production in normal men for a minimum of
15 days (Herbst et al, 2004).
Blood was drawn before 0800 hours for serum T and DHT daily during the
drug-exposure period. In addition, 1, 3, 4, 8, and 10 days after acyline
administration, subjects drank 400 mg of T in oil. On days 1, 3, 4, 8, and 10,
subjects had blood drawn via a heparin-locked IV line at baseline, 0.5, 1, 2,
3, 4, 6, 8, 10, 12, and 24 hours after administration of oral T in oil for
measurement of serum T and DHT. On days 1, 3, and 8, subjects ingested the T
while fasting and did not eat any food until 90 minutes after dosing. On days
4 and 10, subjects ingested the T with a meal of at least 750 kcal, which
included at least 250 kcal (approximately 30 g of fat). Subjects
self-administered the finasteride or dutasteride. On day 2, subjects took 5 mg
of finasteride twice (morning and evening) and then took 5 mg daily for day 3
and day 4 (total dose, 20 mg). On day 7, subjects took 0.5 mg dutasteride
twice (morning and evening) and then took 0.5 mg daily on days 8–10
(total dose, 2.5 mg). We were unable to study the pharmacokinetics of oral
testosterone with food but without concomitant 5 reductase inhibition
as the amount of blood drawn from subjects on a sixth day of draws would have
exceeded the maximum allowable for the 2-week study period. For safety,
subjects underwent daily testing of liver function (aspartate
aminotransferase, bilirubin, alkaline phosphatase), kidney function (urea
nitrogen, creatinine), and hematopoiesis (hemoglobin and hematocrit). Four
weeks after the completion of the drug-exposure period, subjects were examined
and underwent a blood draw for serum hormones to ensure they had returned to
normal. A sample size of 7 subjects was estimated to have an 80% power with an
of .05 to detect a 30% change in serum testosterone area under the
curve between T and T + D or T + F.
Measurements
Serum total T was measured by a radioimmunoassay (Diagnostic Products
Corporation, Webster, Tex) The assay had a sensitivity of 0.35 nmol/L and
interassay variations for low, mid, and high pools of 13.6%, 6.1%, 6.8%, and
intra-assay variation of 10.0%, 5.3%, 6.6%. The normal range was 8.7–33
nmol/L. DHT was measured using an radioimmunoassay (Diagnostic Systems
Laboratory, Los Angeles, Calif). The sensitivity of this assay was 0.043
nmol/L and the intra-assay variation for mid- and low-range pools was 9.9% and
11%, with interassay coefficients of variations of 19% and 25%. The normal
range for serum DHT was 1.0–3.1 nmol/L. The normal ranges for T and DHT
were determined in our laboratory using serum samples obtained from 100 normal
men aged 20–50 years.
Statistics
Average concentration during the 24-hour period after dosing, maximum
concentration after dosing (Cmax), time to maximum concentration
(Tmax), area under the curve (AUC), and elimination phase half-life
(T1/2) were calculated for each subject using a computer program
(PK solutions, Golden, Co). Pharmacokinetic parameters and serum hormone
levels at each time point for each of the 3 fasting days of T administration,
and for the comparison of fasting vs fed days, were compared using the
Wilcoxon sign rank test with a Bonferroni correction for multiple comparisons
(effective , .017). Statistical analyses were performed using STATA
(College Park, Tex). For all comparisons, an of .05 was considered
significant.
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Results |
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Serum Testosterone
In all subjects, serum T levels were suppressed to castrate levels by 24
hours after acyline administration (day zero: T 15.8 ± 6.8 nmol/L vs
1.6 ± 0.9 nmol/L [day 1]; P < .0001). In addition, mean
serum T levels before each dose of T (ie, 24 hours after the previous dose)
were not significantly different from those seen 24 hours after acyline
administration in all cases.
In the fasting state, the combination of oral T in oil and either D or F increased the resulting serum T concentrations compared with T in oil alone (Figure 2A). This difference achieved statistical significance 1 and 6 hours after dosing on the day subjects received T + F and 6 hours after dosing on the day subjects received T + D. There were no significant differences between the elevations in serum T levels seen after oral dosing of T in oil between the T + F and T + D treatment days (P > .05 for all comparisons). The area under the curve of serum T increased significantly with either F or D compared with T in oil alone (P < .05 for both comparisons; Table 2). The maximum concentration of serum T after oral dosing of T in oil with T + F was significantly greater than the maximum with T-alone (50 ± 28 nmol/L [T + F] vs 19.7 ± 9.1 [T-alone]; P = .02) with the maximum concentration of T exceeding the normal range in 5 of 7 subjects with T + F. Time of maximum concentration of serum T after oral dosing of T in oil was nonsignificantly earlier on the T + F and T + D days compared with T-alone. Last, the calculated terminal half-life of serum T after dosing was between 6 and 10 hours regardless of treatment.
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Serum DHT levels
Serum DHT decreased significantly 24 hours after acyline administration
(day 0 DHT: 1.6 ± 0.6 nmol/L vs 0.6 ± 0.2 nmol/L [day 1];
P < .05). In addition, mean serum DHT levels before each dose of T
(ie, 24 hours after the previous dose) were not significantly different from
those seen 24 hours after acyline administration.
In the fasting state, the combination of oral T in oil and either D or F nonsignificantly decreased the resulting serum DHT concentrations compared with T in oil alone (Figure 2B). Moreover, there were no significant differences between the levels of serum DHT levels seen after oral dosing of T in oil with either F or D (P > .05 for all comparisons). The AUC of serum DHT decreased nonsignificantly compared with oral T in oil when combined with either F or D compared with T in oil alone (P > .05 for both comparisons; Table 3). There was a trend toward a decrease in the maximum concentration of serum DHT with T + D compared with the T-alone (8.7 ± 5.5 nmol/L [T + D] vs 15.7 ± 7.6 [T-alone]; P = .06). Time of maximum concentration of serum DHT and calculated terminal half-life of serum DHT after dosing was similar with all treatments.
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Effect of Food Intake
Mean serum T was significantly decreased at 1 hour in the T + F fed vs T +
F fasting group (Figure 3A). In
addition, mean serum T at every other time point with either T + F or T + D
was decreased in a nonsignificant fashion when oral T in oil was administered
with food compared with administration while subjects were fasting
(Figure 3A and B). There was a
trend toward decreases in maximum concentration of T with feeding for both T +
F and T + D, and a trend toward an increase in the time to maximum
concentration of T when the T was administered with food
(Table 2).
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Discussion |
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reductase inhibitor finasteride is as effective at increasing serum T levels
after the administration of an oral dose of T in oil as dutasteride. As in our
prior work with oral T in oil, combining the oral T with a 5 reductase
inhibitor roughly doubles the resulting serum concentrations of T. Therefore,
one can infer that approximately 
of a dose of oral testosterone is
5 reduced in vivo to DHT. This conversion could occur in either the
intestinal lining or the liver, which have both been shown to express 5
reductase (Thigpen et al,
1993). Whether dutasteride, which inhibits both type 1 and 2
5 reductase (Rittmaster,
1997) and results in greater suppression of serum DHT than
finasteride (Clark et al,
2004), may be more effective with long-term administration or oral
T in oil remains to be determined.
The bioavailability of orally administered T has been previously reported to be around 3.5%, due to extensive hepatic metabolism, whereas the bioavailability of oral TU is approximately 6.8% (Tauber et al, 1986). The superior bioavailability of oral TU is likely due to the fact that around 80% of an oral dose of TU is absorbed via the lymphatics (Shackleford et al, 2003), a process that is markedly enhanced by the simultaneous intake of fatty foods (Frey et al, 1979; Bagchus et al, 2003). If oral administration of unesterified T in oil were similarly absorbed via the lymphatics, one might expect food intake to also improve T absorption; however, in our study, the opposite occurred. We observed decreases in maximum concentration of serum T, AUC of T, and a delay to maximum concentration when the oral T in oil was given with food as compared with fasting administration. Because the F and D were dosed before the oral T and food, there is little chance that the food decreased the effect of the F or D. Therefore, it is tempting to speculate that, in contrast with oral TU, oral T in oil is not completely absorbed via the lymphatics. Exactly how oral T in oil is absorbed will require additional study.
Comparison of the results obtained in this study with our original study of
oral T in oil (Amory and Bremner,
2005) demonstrates slightly lower serum T values and a shorter
duration of serum T in the normal range after dosing a 400-mg dose or oral T
in oil by about 25%. While this could represent chance or regression to the
mean, another possible explanation for these differences is that, in this
study, the period of 5 reductase pretreatment for all but 1 of the
treatment days was only 24–48 hours as compared with 72–120 hours
of dutasteride pretreatment in the original study. Indeed, the greatest
reductions in serum DHT levels were seen on treatment day 10, the only study
day in which a 72-hour period of dutasteride pretreatment was employed. This
finding emphasizes the importance of adequate 5 reduction in attaining
therapeutic levels of serum T (without supraphysiologic elevations of serum
DHT) after the administration of oral T in oil and implies that longer-term
studies of these combinations will be required to more accurately determine
the full impact of 5 reduction on the augmentation of serum T levels
after oral administration.
Direct comparison between finasteride and dutasteride in this study is not
possible for several reasons. First, although the half-life of finasteride is
only 12 hours, and there was a 96-hour interval between the last dose of
finasteride on day 4, and the dose of oral testosterone on study day 8, there
may have been residual 5 reductase inhibition from the finasteride
during the second week of the study. This is possible as the biological
activity of finasteride (as assessed by significant DHT suppression) may be
seen for up to 5–7 days after doses of 10–40 mg (Vermuelen et al,
1989). Moreover, because of the long half-life of dutasteride and its relative
potency for type 2 vs the type 1 enzyme
(Clark et al, 2004), it is
likely, at the dose and duration of dutasteride used in this study, that the
dutasteride was mainly inhibiting the type 2 enzyme. If the type 1 5
reductase significantly contributes to the metabolism of oral testosterone,
dutasteride may prove to be a superior drug to finasteride with long-term
administration. Testing this hypothesis will require comparison of the 2 drugs
over longer periods of time.
Importantly, there was no evidence of either liver or kidney toxicity
associated with the doses of oral T administered in this study; however,
longer term study of these doses of T combined with a 5 reductase
inhibitor will be required to determine the safety of this approach to T
therapy. In theory, the ability to selectively increase serum T without
increasing serum DHT may be attractive in minimizing the risk for
DHT-dependent disease, such as prostate hypertrophy, acne, and alopecia
associated with T therapy.
In conclusion, we have demonstrated that single doses of T administered
orally in oil combined with either finasteride or dutasteride can result in
elevated serum levels of T in normal men with experimentally induced
hypogonadism. Such serum T levels would presumably be therapeutically
effective in treating testicular failure. In addition, we have demonstrated
that, in contrast with oral TU, concomitant food intake tends to decrease the
serum T levels observed after administration of oral T in oil. Combinations of
oral T in oil and 5 reductase inhibitors may allow for an oral,
selective form of androgen therapy. Additional studies of the long-term
safety, pharmacokinetics, and pharmacodynamics of these combinations are
warranted to determine if they will be a clinically useful alternative method
to treat T deficiency.
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Acknowledgments |
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Footnotes |
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P < .05 compared with T-alone (T + D).