Vol. 287, Issue 2, 591-597, November 1998
Biotransformation of Tirilazad in Human: 4. Effect of Finasteride
on Tirilazad Clearance and Reduced Metabolite
Formation1
Joseph C.
Fleishaker2 ,
Paul G.
Pearson3 ,
Larry C.
Wienkers,
Laura K.
Pearson,
Theresa A.
Moore and
Gary R.
Peters3
Clinical Pharmacokinetics (J.C.F., L.K.P.),
Drug Metabolism and
Disposition Research (P.G.P., L.C.W., T.A.M.) and
Clinical Development
CNS/Critical Care Unit (G.R.P.), Pharmacia and Upjohn, Inc., Kalamazoo,
Michigan
 |
Abstract |
The effect of oral finasteride, an inhibitor of 5
-reductase, on the
clearance of tirilazad, a membrane lipid peroxidation inhibitor, was
assessed in eight healthy men who received: 1) 10 mg/kg tirilazad
mesylate solution orally on the 7th day of a 10-day regimen of 5 mg
finasteride once daily, 2) 10 mg/kg tirilazad mesylate orally, 3) 2 mg/kg tirilazad mesylate i.v. on the 7th day of a 10-day regimen of 5 mg finasteride once daily and 4) 2 mg/kg tirilazad mesylate i.v., in a
four-way cross-over design. Plasma concentrations of tirilazad and its
active reduced metabolites (U-89678 and U-87999) were measured by
liquid chromatography with tandem mass spectrometry (LC-MS-MS).
Finasteride increased mean tirilazad areas under the curve by 21 and
29% for i.v. and p.o. tirilazad, respectively. Mean U-89678 areas
under the curve were decreased 92 and 75% by finasteride
administration with i.v. and p.o. tirilazad, respectively, and
decreases of 94 and 85% in mean U-87999 area under the curve values
were observed. These differences were statistically significant. These
results indicate that finasteride inhibits the metabolism of tirilazad
to U-89678. However, this inhibition has only a moderate effect on the
overall clearance of tirilazad. These results thus confirm earlier
in vitro work that showed that tirilazad is predominantly
metabolized by CYP3A4. Although the major circulating metabolites of
tirilazad are formed via reduction, this represents a minor route of
tirilazad elimination in man.
| |
Introduction |
Tirilazad
is a membrane lipid peroxidation inhibitor that has been tested in
animal models for the prevention of neuronal damage due to head trauma,
subarachnoid hemorrhage, spinal cord injury and stroke (Braughler
et al., 1989
). Tirilazad has been evaluated clinically in
the same disorders and has demonstrated reduced mortality in male
subarachnoid hemorrhage patients (Haley et al., 1994; Bleck
et al., 1995; Kassell et al., 1993; Kassell et al., 1996).
Tirilazad mesylate appears to be a medium extraction ratio compound
(Fleishaker et al., 1994, 1993). The majority of tirilazad is recovered in the feces as various metabolites; less than 12% of the
dose is recovered in the urine as drug-related materials (Stryd
et al., 1992). One reduced metabolite has been identified that has activity similar to that of tirilazad in a rat model of
subarachnoid hemorrhage (Smith et al., 1996) (U-89678, fig. 1). This metabolite exhibits AUC values
on multiple dosing which may be >50% of those of the parent compound
(Fleishaker et al., 1994). An additional metabolite with
activity in the mouse head injury model, U-87999 (fig. 1) (Smith
et al., 1996) has also been identified in human plasma, but
plasma concentrations of this metabolite are generally <20% than
those of U-89678 (Fleishaker et al., 1996).
Recent experiments in human liver microsome preparations suggest that
the major pathways of tirilazad metabolism in humans are mediated by
the 3A isozymes of cytochrome P-450 (CYP3A) (Wienkers et
al., 1996). These results have been confirmed by the observation that ketoconazole, a specific CYP3A inhibitor, dramatically reduces the
clearance of tirilazad in vivo (Fleishaker et
al., 1996). Despite this fact, the major metabolites of tirilazad
found in circulation are formed via reduction. In rat and human liver
microsomes, 5-reductase was found to mediate the formation of
U-89678 (Wienkers et al., 1995, 1998). This reaction was
inhibited by finasteride, an inhibitor specific for this enzyme. Thus,
administration of finasteride and tirilazad concomitantly might allow
the determination of the relative contribution of 5-reductase to the
elimination of tirilazad in man in vivo.
Our purpose was to determine the relative contribution of
5-reductase to the clearance of tirilazad in healthy volunteers by
administering tirilazad p.o. and i.v. in the presence and absence of
the specific 5-reductase inhibitor, finasteride. Using this approach
we hoped to ascertain the relative contribution of 5-reductase to
the clearance of tirilazad after i.v. administration and determine the
effect of finasteride on the absolute bioavailability of tirilazad after p.o. administration.
| |
Materials and Methods |
Subjects and procedures.
The study was conducted at the
Upjohn Research Clinics, Kalamazoo, MI. The study was approved by the
Bronson Methodist Hospital Institutional Review Board, and each
volunteer provided written evidence of informed consent before enrollment.
Nine male volunteers (ages 18-53, weight 55.3-85.3 kg) were enrolled
in the study; eight subjects completed all study activities. One
subject withdrew from the study for personal reasons. Subjects were
determined to be in good health by physical examination and standard
clinical laboratory tests. Subjects received no known enzyme inducing
agents for 30 days before the study, no medications during the 7 days
before the study and no alcohol for 2 days before and throughout the
study. During the course of the study, subjects were to receive no
medications other than those specified in the protocol.
Subjects received the following treatments according to a randomized
four-way crossover design: 1) 5-mg finasteride tablet given p.o. at
06:00 on days 1 to 10 and 10 mg/kg tirilazad mesylate solution (1.5 mg/ml) given orally on day 7 at 08:00, 2) 10 mg/kg tirilazad mesylate
solution given orally on day 7 at 08:00, 3) 5-mg finasteride tablet
given orally at 06:00 on days 1 to 10 and 2 mg/kg tirilazad mesylate
solution given i.v. on day 7 at 08:00 and 4) 2 mg/kg tirilazad
mesylate solution given i.v. on day 7 at 08:00. Oral tirilazad was
administered via orogastric tube; i.v. tirilazad was administered after
1:2 dilution with normal saline as a 10-min infusion. Tirilazad
administration on day 7 occurred after an overnight fast. A 1-wk
wash-out period separated study phases.
Clinical assessments.
A 12-lead electrocardiogram was
recorded pre-dose on day 
1, before the tirilazad dose on day 7 and on
day 8 (24 hr after the tirilazad dose) in each study phase. A blood
sample for the determination of safety laboratories (hematology and
chemistry) was collected on day 1 of phase I and day 11 (24 hr after
the last finasteride dose) of phase IV. Additional blood samples for the determination of alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin, and 
-glutamyl transferase (GGT) were collected on days 1, 7 and 11 of the phases in which subjects received
treatments A and C (finasteride + tirilazad treatments). A blood
sample was drawn pre-dose on days 1 and 7 of each phase for
dihydrotestosterone determinations. Subjects were interviewed before
dosing and on the evening of each study day to determine whether they
had experienced any medical events.
Blood sampling.
Venous blood samples for the determination
of tirilazad (7 ml) were collected into heparinized vacutainers
immediately prior to drug dosing on day 7 and again at 12, 15, 30 and
40 min and at 1.0, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72 and 96 hr after
the start of tirilazad administration. Plasma was harvested from the samples after centrifugation and frozen at 70°C until analyzed.
Analytical methods.
Plasma concentrations of tirilazad,
U-89678 and U-87999 were determined by a sensitive and specific
LC-MS-MS method. After plasma protein precipitation using acetonitrile
containing internal standard
(13C3,15N2-U-74006F),
the supernatant was injected on an high-performance liquid
chromatography system consisting of a mobile phase of methanol:water: 5 M ammonium acetate pH 6.0 (85:10:5, v:v:v) flowing at 1.2 ml/min through a Kromasil 100-5C18 column (150 mm × 4.6 mm i.d.). The detector, a Finnegan TSQ-700 triple quadrupole mass spectrometer, was
coupled to the LC system via an atmospheric pressure chemical ionization source. The protonated molecular (M+H) ion for tirilazad at
m/z 625 and the stable isotope at m/z 630 were transmitted and the
product ion fragments monitored at m/z 260 and 265, respectively. Molecular ions for PNU-87999 at m/z 629, PNU-89678 at m/z 627 and
PNU-76824 at m/z 634 were transmitted and product ion fragments at m/z
260 were also monitored.
For tirilazad, the assay was linear over the range of 0.45 to 10490 ng/ml. The precision of the system, expressed as the CV of the slope of
the standard curves, was ±3%. The precision of the method, expressed
as the mean CV of the back-calculated calibration standard
concentrations, was ±5.2%. For the quality control (QC) samples, mean
recoveries were 107 ± 9, 112 ± 5 and 105 ± 5% for the low, medium and high concentration controls, respectively.
For U-89678, the assay was linear over the range of 0.47 to 988 ng/ml.
The precision of the system, expressed as the CV of the slope of the
standard curves, was ±15%. The precision of the method, expressed as
the mean CV of the back-calculated calibration standard concentrations,
was ±5.9%. For the QC samples, mean recoveries were 89 ± 6, 93 ± 7 and 97 ± 7% for the low, medium and high
concentration controls, respectively.
The assay was linear for U-87999 over the range of 0.51 to 970.5 ng/ml.
System precision, expressed as the CV of the slope of the standard
curves, was ±11%. The mean CV of the back-calculated calibration
standard concentrations was ±6.8%. For the QC samples, mean
recoveries were 88 ± 6, 89 ± 8 and 93 ± 7% for the
low, medium and high concentration controls, respectively.
Data analysis.
Pharmacokinetic parameters were determined by
noncompartmental methods (Gibaldi and Perrier, 1982). The 
z was
determined by linear regression of the terminal portion of the
concentration-time profile. The terminal t1/2 was
calculated as 0.693/z. AUC0-
was determined by trapezoidal rule
up to the last time at which a measurable concentration was observed
and extrapolated to infinity. AUMC0- for tirilazad was determined
in an analogous manner. MRT after the i.v. administration of tirilazad
was calculated as AUMC0-/AUC0- T/2, where T is the infusion
duration. CL of tirilazad was calculated as dosei.v./AUC0-i.v. CLPO
was calculated in an analogous manner. Vss after the i.v. dose of
tirilazad was calculated as CL · MRT. Tirilazad Cinf
(concentration at the infusion stop), Cmax of U-89678, U-87999 and
tirilazad (after oral dosing) and the Tmax at which they occurred were
determined by inspection of the plasma concentra-tion-time profile. The
F of tirilazad was calculated as (AUC0-PO dose
i.v.)/(AUC0-
i.v. DosePO).
Effects of treatment on pharmacokinetic parameters of tirilazad,
U-89678, and U-87999 were assessed using ANOVA for a cross-over model.
Due to nonhomogeneous variances among treatment groups, ranks rather
than the raw data were used for this analysis. The subject number was
selected to provide an 88% power to detect a 40% difference in
tirilazad AUC0- given a 20% CV from the ANOVA and an level of
0.05. The actual CV from this study was 19.9%, yielding a power of
90% to detect the above difference in AUC0-. Pair-wise comparisons
within routes of administration were performed by Waller-Duncan K-ratio
t test (Waller and Duncan, 1969). The method requires equal
sample sizes in each treatment group, and the degree of conservatism of
the test varies with the heterogeneity of the data (Milliken and
Johnson, 1984). This test is thus amenable to the data collected in
this study.
| |
Results |
Clinical.
Tirilazad administration was well tolerated by both
routes of administration in this study. As expected, local injection
site discomfort was frequent with i.v. administration. With p.o.
tirilazad administration, some reports of nausea and/or dyspepsia were
temporally related to dosing. All of these events were transient and
mild or moderate in intensity. Finasteride administration was also well
tolerated and did not appear to affect the medical event profile of
tirilazad. No clinically important alterations in electrocardiogram or
laboratory parameters were observed with either drug.
In the treatments in which finasteride was administered, plasma
dihydrotestosterone was decreased 36% (p.o. tirilazad) and 40% (i.v.
tirilazad) on day 7 of the treatment phase relative to baseline levels.
These changes were statistically significant. In the treatments in
which tirilazad alone was administered, dihydrotestosterone concentrations increased 14% in both p.o. and i.v. treatments (also
statistically significant).
Pharmacokinetics.
Plasma concentrations of tirilazad are shown
in figure 2. Mean pharmacokinetic
parameters for tirilazad are listed in table 1. Individual values for AUC0- and
subject weight are provided in table 2.
The absolute oral bioavailability of tirilazad was 0.091 ± 0.029. In the presence of finasteride, this value was 0.083 ± 0.029. Mean tirilazad AUC0- was increased 21 and 29% by finasteride
administration during i.v. and oral administration of tirilazad,
respectively. After p.o. tirilazad, mean tirilazad Cmax was
increased 11% by finasteride coadministration. Only the change in
tirilazad AUC0- after i.v. tirilazad was statistically significant,
but finasteride decreased tirilazad clearance significantly after both
i.v. and p.o. tirilazad administration. Tmax after oral tirilazad was
not significantly affected by finasteride administration. Neither
half-life or volume of distribution after i.v. tirilazad administration
was affected by finasteride administration. For p.o. tirilazad,
terminal half-life was unaffected by finasteride coadministration.
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Fig. 2.
Mean plasma concentrations of tirilazad mesylate
after the administration of p.o. and i.v. tirilazad in the presence and
absence of finasteride coadministration.
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TABLE 1
Mean (±S.D.) pharmacokinetic parameters for tirilazad mesylate (TM)
after administration of 2.0 mg/kg tirilazad mesylate i.v. and 10 mg/kg
of tirilazad mesylate p.o. in the presence and absence of 5 mg
finasteride coadministration
|
|
Plasma concentrations of U-89678 are depicted in figure
3; mean pharmacokinetic parameters for
this metabolite are shown in table 3.
Coadministration of finasteride resulted in 92 and 75% decreases in
the apparent AUC0- of U-89678 after i.v. and p.o. administration of
tirilazad, respectively. Cmax was decreased 95 and 91% after i.v. and
p.o. tirilazad, respectively, during finasteride administration. All of
these differences were statistically significant. Mean U-89678 Tmax
values after p.o. and i.v. tirilazad were significantly longer when
finasteride was coadministered.
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Fig. 3.
Mean plasma concentrations of U-89678 after the
administration of p.o. and i.v. tirilazad in the presence and absence
of finasteride coadministration.
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TABLE 3
Mean (±S.D.) pharmacokinetic parameters for U-89678 after
administration of 2.0 mg/kg tirilazad mesylate (TM) i.v. and 10 mg/kg
of tirilazad mesylate p.o. in the presence and absence of 5 mg
finasteride
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|
Plasma concentrations of U-87999 are depicted in figure
4; mean pharmacokinetic parameters are
listed in table 4. Due to the fact that
terminal half-life for this metabolite could not be determined in the
majority of subjects in the finasteride treatments, AUC0-96 was
calculated instead of AUC0-. As with U-89678, administration of
finasteride significantly decreased AUC0-96 and Cmax of U-87999 after
p.o. and i.v. tirilazad administration.
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Fig. 4.
Mean plasma concentrations of U-87999 after the
administration of p.o. and i.v. tirilazad in the presence and absence
of finasteride coadministration.
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TABLE 4
Mean (±S.D.) pharmacokinetic parameters for U-87999 after
administration of 2.0 mg/kg tirilazad mesylate (TM) i.v. and 10 mg/kg
of tirilazad mesylate PO in the presence and absence of 5 mg
finasteride
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| |
Discussion |
Tirilazad administration was well tolerated in male volunteers by
both routes of administration in this study. As expected, local
injection site discomfort was frequent with i.v. administration. With
p.o. tirilazad administration, some reports of nausea and/or dyspepsia
were temporally related to dosing. Finasteride administration did not
appear to affect the medical event profile of tirilazad.
The purpose of this trial was to assess the effect of finasteride on
the pharmacokinetics of tirilazad after i.v. and p.o. administration of
tirilazad mesylate. These data were to help in assessing the relative
clearance of tirilazad by oxidative and reductive routes. According to
the well-stirred model of hepatic clearance (Wilkinson and Shand,
1975), hepatic clearance can be described as:
|
(1)
|
where Q is hepatic blood flow and E is the extraction ratio.
Because tirilazad does not partition into erythrocytes, CLh and Q will
refer to plasma clearance and hepatic plasma flow, respectively,
throughout the remainder of the discussion. The fractional
availability through the liver (Fh) is described as:
|
(2)
|
The well stirred model describes the extraction ratio as:
|
(3)
|
where CLint is the intrinsic clearance.
Previous results indicate that tirilazad is metabolized predominantly
by CYP3A to various hydroxy metabolites (Wienkers et al.,
1996), but that U-89678, the major circulating metabolite is formed by
5-reductase (Wienkers et al., 1995, 1998). Rearranging equation 1 and using a value of 54 liter/hr for hepatic plasma flow
(liver blood flow × 0.6), the extraction ratio of tirilazad is
calculated from the systemic clearance of tirilazad after i.v. administration to be 0.56 and 0.48 in the absence and presence of
finasteride administration, respectively. By rearranging equation 3 and
substituting the above values for the extraction ratio, it is apparent
that intrinsic clearance of tirilazad in the liver decreased from 68.7 to 49.8 liter/hr, or decreased by approximately 28%. Mean AUC0-'s
of the two reduced metabolites were reduced much more substantially by
finasteride coadministration. Therefore, the results of this study
confirm that 5-reductase is responsible for the formation of U-89678
in vivo in man.
By considering our results in light of the results of the previous
tirilazad, ketoconazole interaction trial (Fleishaker et al., 1996), it is possible to address the relative importance of
5-reductase in the clearance of tirilazad. Ketoconazole, a specific
3A inhibitor, has no effect on 5-reductase activity. Finasteride,
although it is metabolized by CYP3A4 (Huskey et al., 1995),
appears to have little effect on cytochrome P-450 activity (Winchell
et al., 1993). Therefore, by considering the residual intrinsic clearance of tirilazad in the presence of these specific inhibitors, we may assess the relative importance of these routes of
metabolism. In the presence of ketoconazole, the intrinsic clearance of
tirilazad is reduced from 68.7 to 28.4 liter/hr. Therefore, if one
assumes that metabolism via CYP3A is completely blocked by
ketoconazole, the intrinsic clearance by non CYP3A pathways would be
28.4 liter/hr. In our study, the intrinsic clearance of tirilazad was
reduced by approximately 18.9 liter/hr by finasteride administration.
The evidence from this study suggests that 5-reductase may not have
been completely blocked by finasteride, because dihydrotestosterone levels were reduced by a maximum of 40% compared to the 61 to 63%
reported after 7 days of administration of finasteride at doses of 1 and 10 mg/day, respectively, to healthy volunteers (Ohtawa et
al., 1991). Thus, it is not possible to determine exactly the
relative contributions of CYP3A and 5-reductase to the metabolic clearance of tirilazad. However, the results of these two studies confirm the results of in vitro work that shows that
tirilazad is predominantly metabolized by CYP3A. Although the major
circulating metabolites of tirilazad are formed via 5-reductase,
this represents a minor route of tirilazad metabolism in man. These
conclusions are represented schematically in figure
5, which outlines the most important
pathways for tirilazad metabolism in man.
The results after oral administration show that the absolute
bioavailability of tirilazad is unaffected by finasteride
administration; however, to consider this further, one should take into
account those factors that can affect oral bioavailability. The factors that affect F have been described by the following equation (Hebert et al., 1992):
|
(10)
|
where Fa is the fraction absorbed and Fg is the fractional
availability through the gut. Because the fractional absorption of
tirilazad in man is not known, we can only determine the product of Fa
and Fg in this study. Previous results suggest that tirilazad undergoes
substantial gut wall metabolism (Fleishaker et al., 1996).
Using the values described above for Fh and for F from table 1, the
product of Fa and Fg is calculated to be 0.18 and 0.17 in the absence
and presence of finasteride, respectively. If one assumes that
finasteride does not affect tirilazad absorption, this result indicates
5-reductase does not substantially contribute to the presystemic
metabolism of tirilazad in the gut.
Subarachnoid hemorrhage is an event that occurs most commonly in the
middle-age population. Males in this age group are also at risk to
develop prostatic hypertrophy; thus, tirilazad and finasteride may be
administered concomitantly. In the absence of finasteride treatment,
the AUC0- of U-89678 was 27% of that of tirilazad after i.v.
treatment. Although finasteride blocked formation of U-89678 and
drastically reduced its AUC0-, tirilazad AUC0- after
coadministration of finasteride and i.v. tirilazad increased
approximately 21%. Therefore, the total exposure to active materials
in plasma was similar in the presence and absence of finasteride
administration. The clinical significance of this interaction is thus
expected to be minimal.
| |
Footnotes |
Accepted for publication May 6, 1998.
Received for publication January 26, 1998.
1
This work was supported financially by Pharmacia and
Upjohn, Inc.
2
Current address: Merck and Co., West Point, PA.
3
Current address: Astra Pharmaceuticals LP Wayne, PA.
Send reprint requests to: Dr. Joseph C. Fleishaker,
Clinical Pharmacokinetics Unit, 7215-24-205, Pharmacia and Upjohn,
Inc., Kalamazoo, MI 49007.
| |
Abbreviations |
SAH, subarachnoid hemorrhage;
t1/2, half-life;
AUC0-, area under the plasma
concentration-time curve;
AUMC0-, area under the first moment
curve;
MRT, mean residence time;
T, infusion duration;
CL, systemic
clearance;
CLPO, oral clearance;
Vss, volume of distribution at
steady-state;
Cinf, concentration at the end of infusion;
Cmax, maximal
plasma concentration;
Tmax, time of maximal plasma concentration;
F, absolute bioavailability;
ANOVA, analysis of variance;
E, extraction
ratio;
Fh, fractional availability through the liver;
Fa, fraction
absorbed;
Fg, fractional availability through the gut;
CLint, intrinsic
clearance;
Q, hepatic blood flow;
CLh, hepatic clearance;
CV, coefficient of variation;
z, terminal elimination rate constant.
| |
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Abstract
Introduction
