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D-penicillamine in patients with rheumatoid arthritis serum levels pharmacokinetic aspects and correlation with clinical course and side effects.

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1362
D-PENICILLAMINE IN PATIENTS WITH
RHEUMATOID ARTHRITIS
Serum Levels, Pharmacokinetic Aspects, and Correlation with Clinical
Course and Side Effects
A. 0. MUIJSERS, R. J. V A N DE STADT, A. M. A. HENRICHS,
H. J. W. AMENT, and J. K. V A N DER KORST
After administration of D-penicillamine to patients with rheumatoid arthritis, measurements of serum level and urinary excretion showed half-life times of
1.6 hours in the rapid phase and 4-6 days in the slow
phase. The latter evidence suggests that tissue pooling
occurs. With a dosage of 750 mglday, basic serum levels
of 100 pM are gradually reached. Serum D-penicillamine levels were shown to be the same for patients who
responded well to treatment, those who did not respond,
and for patients who had adverse side effects as well as
those who had none. Intestinal resorption decreased
when D-penicillamine was taken close to meals and was
greatly reduced by iron preparations.
For several decades D-penicillamine (p,pdimethylcysteine) has been established as an essential
drug in the treatment of Wilson’s disease (1-3) and
cystinuria (2-5). It has also had limited application in
conditions such as heavy-metal poisoning (3,6), primary biliary cirrhosis (3,7), and chronic juvenile polyarthritis (3,8). During the last 10 years, D-penicillamine has become one of the major second-line drugs
From the Jan van Breemen Institute, Amsterdam and the
Laboratory of Biochemistry, B. C. P. Jansen Institute, University of
Amsterdam, The Netherlands.
Supported by a grant from The Netherlands League against
Rheumatism and, during the initial stage of investigation, by Merck
Sharp & Dohme, The Netherlands.
A. 0. Muijsers, PhD: Biochemist, B. C. P. Jansen Institute;
R. J. van de Stadt, PhD: Biochemist; A. M. A. Henrichs: Research
Technician; H. J. W. Ament, MD: Rheumatologist; J. K. van der
Korst, MD: Scientific Director, Jan van Breemen Institute.
Address reprint requests to Dr. J. K. van der Korst,
Scientific Director, Jan van Breemen Institute, Dr. Jan van Breemenstraat 2, 1056 AB, Amsterdam, The Netherlands.
Submitted for publication January 24, 1983; accepted in
revised form June 26, 1984.
Arthritis and Rheumatism, Vol. 27, No. 12 (December 1984)
for the treatment of rheumatoid arthritis (RA) (2,3,9).
Although the efficacy of D-penicillamine treatment in RA patients has been demonstrated, as yet the
mechanism of action is undetermined. In order to
evaluate the likelihood of the proposed mechanisms
(based on experiments in vitro), it is essential to know
the concentrations of D-penicillamine that are reached
during therapy. Current knowledge of the pharmacokinetics of D-penicillamine, however, is fragmentary. Dpenicillamine is difficult to measure because it is labile
and reactive. Measurement is further complicated by
the presence of metabolic products such as penicillamine disulfide, mixed disulfides with both cysteine and
protein thiol groups, and S-methylpenicillamine (10).
We have developed a method for determining
D-penicillamine levels in biologic fluids (1 1) and now
report some pharmacokinetic data, portions of which
have been previously reported in preliminary form
(12,13), obtained in RA patients and healthy volunteers. Our data, combined with the results reported by
other groups (10,14-19) who have recently developed
methods for determining D-penicillamine levels (mostly by high performance liquid chromatography), provide a more detailed analysis of the concentration of
the drug in vivo.
We also present here our data on the factors
that affect resorption of the drug as well as a possible
relationship between the serum concentrations of both
D-penicillamine and cysteine and the clinical response
and occurrence of severe side effects during treatment.
PATIENTS AND METHODS
Determination of D-penicillamine and cysteine levels
in serum and urine samples was performed as previously
1363
D-PENICILLAMINE IN RA
described (1 1). Samples were obtained and kept frozen until
testing. Samples were oxidized with performic acid, without
prior deproteinization, to convert penicillamine and cysteine
derivatives to D-penicillamine acid and cysteic acid, respectively. Quantification was performed with an automatic
amino acid analyzer (Multichrom B and Multichrom M,
Beckman, Munich, FRG) using a column of Aminex A25
anion exchange resin (Bio-Rad, Richmond, CA). This assay
measures the sum of the free thiol form of D-penicillamine
plus the penicillamine present in mixed disulfides with
cysteine and protein, and also measures the D-penicillamine
originally present in metal chelates. In this report, the term
“D-penicillamine” includes all these forms. Accordingly,
the term “cysteine” includes cystine and the cysteine residues bound in mixed disuffide linkage.
D-penicillamine was obtained from Sigma, St. Louis,
MO, and was administered as 250 mg Kelatin tablets (GistBrocades, Delft, The Netherlands).
All 50 patients who participated in this investigation
had definite rheumatoid arthritis according to the American
Rheumatism Association criteria (20), and in most cases,
their disease was progressive. Many of these patients had
previously received treatment with gold salts. All patients
receiving long-term D-penicillamine therapy also participated in a prospective study on the immunologic side effects of
this treatment, and their clinical courses were closely examined at regular intervals. Closely monitored short-term studies were performed on hospitalized patients.
Standard therapy with D-penicillamine was given
according to the following schedule: 250 mglday for the first
4 weeks, 500 mglday for the second 4 weeks, and then 750
mglday, if necessary. Deviations from this schedule occurred frequently for such clinical reasons as occurrence of
objective and subjective side effects. Response to D-penicillamine was determined by an experienced rheumatologist,
based on clinical and laboratory data.
The studies on the influence of food and iron on the
resorption of D-penicillamine were performed on the authors
as healthy volunteers.
I
days
RESULTS
Figure 1. Pharmacokinetics of a single oral dose of 1,000 mg Dpenicillamine (PEN). The cysteine (cys) serum concentration (upper
half) and urinary excretion (lower ham were recorded for 2 days
before Dpenicillamine was administered on the third day, after
breakfast. The serum concentration of penicillamine is plotted in the
upper half of the figure, the urinary excretion in the lower half. The
time scale for day 3 has been expanded for clarity. Urinary excretion
is plotted from the abscissa downwards.
Pharmacokinetics. Approximately 3 hours after
a single oral dose of D-penicillamine, a maximum
serum level was reached (Figure 1). The level of this
peak increased with increasing dosage (12). The decrease of the D-penicillamine serum concentration after the maximum had been reached was clearly biphasic, as shown in Figure 1 (the time scale for the first 24
hours after a single oral dose is expanded for clarity).
Twenty to thirty percent of the administered dose was
rapidly excreted in the urine in the form of disulfides.
It should be noted that the amounts and concentrations of D-penicillamine presented in Figure 1 are the
sum of the free thiol and disulfide forms.
The lower section of Figure I , in which the
amounts of cxcreted D-penicillamine and cysteine
have been plotted, shows a temporary drop in the
cysteine level. The reason for this drop is clear from
calculations from experiments of this type, which
suggest that about half of the D-penicillamine excreted
is in the form of disulfide mixed with cysteine.
The results of daily repetition of the oral Dpenicillamine dose are shown in Figure 2. The curve of
the serum concentration of D-penicillamine followed a
saw-tooth pattern, while the basic level steadily increased. The cysteine drain could no longer be replenished, and the serum cysteine concentration remained
lowered, with a pattern that was inverse to that of Dpenicillamine. The urinary excretion of D-penicillamine remained constant at about 25% of the dose and
did not increase, showing that the deep D-penicillamine pool was not readily saturated.
MUIJSERS ET AL
1364
PEN
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serum level at the end of treatment could be traced for
weeks. From the traces shown in Figure 3B, apparent
half-lives of 4-6 days were found. Similar values could
be calculated from the urinary excretion pattern.
In order to determine the degree of proteinbinding of the readily accessible serum pool of Dpenicillamine, and to determine how much proteinbound D-penicillamine is present in low molecular
weight forms, pooled serum samples from treated
patients were separated on Sephadex G-50 columns.
From the results of 3 such runs it was determined that
84 k 1.7% of the penicillamine elutes with the void
volume, whereas 16 k 1.6% is present in low molecular weight forms. When the serum sample was treated
with P-mercaptoethanol prior to chromatography,
nearly all D-penicillamine eluted in the low molecular
weight form. This suggests that D-penicillamine in
serum is largely protein-bound.
Correlation with clinical effect. As shown in
Figure 4,there was a tendency toward higher serum Dpenicillamine concentrations after continued treatment. The scatter seems to indicate large differences
between patients, but these differences may be influenced by fluctuations in the time interval between
blood sampling and the preceding drug administration.
Furthermore, strict compliance with the prescribed
Figure 2. Effect of a repeated daily dose of 500 mg D-penicillamine
(PEN) (from day 3 onwards) in a patient with rheumatoid arthritis.
The upper half shows the concentration of penicillamine and cysteine (cys) in serum, the lower half shows the total daily urinary
penicillamine and cysteine excretion. Serum levels were measured
twice a day, just before and 3 hours after penicillamine administration. Penicillamine was given 2 hours before breakfast. Urinary
excretion is plotted from the abscissa downwards.
The single-dose experiments enabled us to estimate the rapid phase of the elimination of D-penicillamine from plasma. As shown by the semilogarithmic
plots in Figure 3A, the initial decrease of the serum
concentration of D-penicillamine showed a half-life of
1.6 hours, which could also be calculated from the
amounts of D-penicillamine excreted in the urine. The
additional amount of cysteine excreted in the urine
after administration of D-penicillamine also declined
with the same half-life. In some patients, the apparent
half-life for the rapid phase was up to 4 hours (data not
shown).
The slow phase of the drug elimination could
best be studied in those patients whose D-penicillamine treatment was terminated after prolonged administration. The decrease of the high D-penicillamine
z? &
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l
4
6
L
8
time (h)
,a- 2
4
6
8
10
12
14
z?
time (days)
Figure 3. A, Fast phase of D-penicillamine (PEN) elimination (in 1
subject) after a single oral dose of 1 ,OOO mg. Serum PEN concentration (0-0); urinary PEN excretion (0------0);
urinary cysteine
excretion (0----0). Urine was pooled over times indicated by
horizontal bars. B, Slow phase of D-penicillamine elimination (in 2
patients) after termination of long-term treatment. The last dose
was given at time zero. First patient: serum PEN concentration
(0-0); urinary PEN excretion (0----0).Second patient: serum
PEN concentration (04);
urinary PEN excretion (04).
Urine was pooled over times indicated by horizontal bars.
1365
D-PENICILLAMINE IN RA
cumulative dose penicillamine (g)
200
20
40
60
80 100 120
€ 1
3
0
0
0
o:
norwesponder
h
112
O
116
1
0
mucocutan. lesions
;O
weeks
;4
i8
I
Figure 4. Serum D-penicillamine (PEN) concentration, measured
just before another dose, plotted against the cumulative dose, for
patients receiving standard treatment. The non-linear beginning of
the time scale is due to the gradual dosage increase to 750 mgiday.
Patients who responded to penicillamine treatment and did not
develop serious side effects are compared with those who responded
but developed either thrombocytopenia, proteinuria, or mucocutaneous lesions. None of the 4 nonresponders included in this figure
developed these side effects.
dosage schedule is assumed but cannot be proven for
outpatients.
The values for the 4 patients classified as nonresponders fall into the range for the patients responding well to treatment. Data from patients with an
inadequate response to D-penicillamine were not included in Figure 4; they were similar to those of the
other groups. A plot of the serum D-penicillamine
concentration versus the cumulative dose (or time)
was the same for male and female RA patients (data
not shown). Figure 4 also shows that there was no
relationship between the serum D-penicillamine level
and the occurrence of 3 of the most pronounced side
effects, thrombocytopenia, proteinuria, and mucocutaneous lesions.
In a preliminary investigation (13) we noticed a
significant correlation between the serum cysteine
levels and the occurrence of side effects. Patients
whose cysteine levels were lowest during the first
weeks after D-penicillamine treatment was started
appeared to show the highest incidence of severe side
effects later on.
Data from a larger number of patients (Figure 5 )
show that after some 8 weeks of treatment, patients
o
no side effects
t hr ombocy t openi a
o
mucocutan. Lesions
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-
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ul
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V
CT
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0 0
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0 0
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0
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~ O - A , ~ O
20 -
0
A
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0
0
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....
,. .
..
II
0
0
0
Ao
O 0
A
i
n
0
A
0
lot
1
I
weeks
12
Figure 5. Decrease of the serum cysteine (cys) concentration during the initial phase of treatment with D-penicillamine. Comparisons
are of patients who had no serious side effects versus patients who
developed severe side effects during or after the time period shown.
Cysteine concentrations were measured at their relative maximum,
just before another dose of D-penicillamine.
MUIJSERS ET AL
1366
Table 1. Intestinal resorption of D-penicillamine as demonstrated by measurements of peak serum
concentration and 48-hour urinary excretion after a single oral dose of D-penicillamine (1,000 mg)*
Subject (sex/age/weight in kg)
S (M/36/75)
H (F/33/50)
M (M/43/75)
Time DSerum
Urinary
Serum
Urinary
Serum
Urinary
penicillamine concentration
excretion
concentration
excretion
concentration
excretion
was taken
(pghnl)
(mgl48 hours)
(p+g/ml)
(mg/48 hours)
(&ml)
(mg/48 hours)
3 hours before
breakfast
With breakfast
2 hours after
dinner
With breakfast
+ iron
12.3
10.6
8.8
364
259
257
10.4
8.0
292
233
15.4
9.6
379
270
ND
25 1
ND
208
ND
158
3.0
38
1.1
85
ND
ND
* Two independent experiments were conducted on subject S for the “with breakfast” category. ND = not
done. Iron was taken in the form of ferrous fumarate (600 mg).
than taking it 2 hours after dinner, which seemed to be
widely practiced. When D-penicillamine was taken
under fasting conditions, the serum peak value was
reached after 3 hours; when taken with a meal, the
(lower) maximum was reached after 2 hours (data not
shown).
Considering the low hemoglobin values that
have been observed in RA patients, it is conceivable
that these patients are taking D-penicillamine and iron
preparations at the same time. As shown in Table 1 ,
this leads to drastic reduction of serum concentration
and urinary excretion of D-penicillamine. The significant effects of the iron on resorption of the drug
suggest that even small doses of iron will affect Dpenicillamine resorption.
DISCUSSION
Our finding of a serum peak value occurring 2-3
hours after administration of a single oral dose of Dpenicillamine correlates with results of other studies
(14,16,17,19). In experiments using 14C-labeled Dpenicillamine in rats, a biphasic loss of plasma label
occurred (21,22). Similar results were obtained with
human volunteers, showing a rapid elimination phase
and a slow phase with a half-life of 8 days (14).
In contrast to radiolabel studies, in which the
data include all penicillamine metabolites, the method
of Saetre and Rabenstein (15) directly identifies the
free thiol form. Using this approach, several groups
(16,17,19,23,24) reported half-life for D-penicillamine
in plasma and urinary excretion to be from 1-5 hours.
Our data, which revealed a half-life of 1.6-3 hours in
the rapid phase, are in accordance with these values.
In these latter 5 studies, the very slow elimination
phase for which we found a half-life of 4-6 days was
not reported.
Despite the differences in the compounds actually measured, it is clear that our kinetic results are
compatible with those in the literature. This suggests
an equilibrium among the different forms in which the
drug is present in the body. Thus, the half-life we
observed for serum D-penicillamine may largely reflect the decrease of the D-penicillamine-albumin
mixed disulfide, while the half-life observed for urinary excretion reflects the appearance of penicillamine
disulfide plus cysteine-penicillamine in the urine.
Since D-penicillamine occurs in different forms in the
body, and since the forms in plasma are different from
those excreted in urine, Crawhall and coworkers (25)
have questioned the use of the term “half-life” in
these measurements.
Our conclusion that up to half of the D-penicillamine excreted in the urine of RA patients is in the
form of cysteine-penicillamine mixed disulfide corresponds to other published reports (10,18). All our RA
patients treated with D-penicillamine showed a drastic
reduction in the total serum cysteine plus cystine
concentration. The physiologic consequences, if any,
of this cysteine drain are not known. The correlation
between the rate of decrease in serum cysteine concentration and the subsequent occurrence of several
side effects, which we initially observed (13), has
become marginal based on study of a larger group of
patients. Munthe and coworkers (26,27) found that
some nonresponders to D-penicillamine treatment
could be converted to responders by suppletion of Lcysteine.
The results of our gel filtration experiments,
D-PENICILLAMINE IN RA
that more than 80% of the D-penicillamine in the
serum of RA patients is bound to protein, correspond
to results obtained by several other groups (5,18,22,28)
in studies of patients with RA and with cystinuria.
However, Bergstrom et a1 (17) suggested that Dpenicillamine cannot be highly and tightly bound to
plasma proteins.
Saetre and Rabenstein (15) reported the presence of 1 1 p M of free thiol and 23 p M of low molecular
weight disulfides in plasma, when D-penicillamine was
administered at a dosage of 750 mg per day. Most
authors agree that the free thiol form is the active
form; however, it seems that full therapeutic benefits
cannot be attributed to the free thiol because it occurs
at such low concentration (approximately 10 CLM). In
contrast to Wiesner et a1 (16), we believe the plasma
protein-bound D-penicillamine (80 pM), because of its
rapid exchangeability, can also be utilized by the
body. Moreover, even the deep pool that is reversibly
bound to tissue becomes available again, albeit slowly,
having a half-life of 4-6 days.
In most hypotheses that attempt to explain the
efficacy of D-penicillamine treatment in rheumatoid
arthritis patients, it is assumed that the free thiol form
or a copper-penicillamine complex is the active form
(29,30). However, the issue has not yet been settled,
and it is still conceivable that the penicillamine bound
in disulfides also plays a role, either directly or via
redox equilibria.
Our finding that the basic serum D-penicillamine level gradually increases during prolonged therapy (Figures 2 and 4) and slowly decreases upon
termination of treatment (Figure 3) is evidence for
accumulation of D-penicillamine, but the location of
the deep pool cannot be inferred from these data. The
fact that the percentage of the drug that is excreted in
the urine does not increase upon continued treatment
shows that the deep pool is not easily saturated. It is
tempting to suggest a direct link between the slow
onset of the therapeutic effect of D-penicillamine in
RA and the slow accumulation of a deep pool in the
body. Although the slow D-penicillamine pool is probably protein-bound, we have determined that it is not
the penicillamine that is bound to serum albumin since
that form was included in our determination of the Dpenicillamine serum concentration. The evidence for
accumulation of D-penicillamine in the connective
tissue of RA patients is indirect and based on studies
with rats (14,21). After a single oral dose of
''C-penicillamine, Perrett (3 I ) recovered only 85% of
the label in urine plus feces, but he suggested that
1367
counting errors might be responsible for the missing
15%.
One major conclusion from our study is that, in
terms of total serum D-penicillamine concentration, no
difference exists between those who respond well to
therapy and those who do not respond. This implies
that in the cases presented, the lack of response was
not caused by insufficient intestinal resorption of the
drug. Since in RA, neither the therapeutic mechanism
nor the precise site of action of D-penicillamine is
known, no further conclusions can be drawn. Further,
the patients who eventually develop one of the major
side effects (proteinuria, mucocutaneous lesions, or
thrombocytopenia) do not show serum D-penicillamine patterns that are significantly different from
those of patients without side effects. The same observation has been made with other slow-acting drugs
such as gold salts (32,33).
A major reason for the low urinary excretion of
oral doses of D-penicillamine is the incomplete intestinal resorption, as has been shown by Perrett in his
balance study with 14C-penicillamine(3 1). The same
conclusion can be drawn from the comparisons of oral
and intravenous dosage conducted previously by us
(34) and more recently by others (16). In a report in
1972 ( 3 3 , it was shown that rats absorbed more Dpenicillamine when fasting than when ingesting the
drug with food. Our suggestion that food interferes
with D-penicillamine resorption in RA patients (12)
was confirmed by Perrett (18), who found that most
RA patients excreted more D-penicillamine when it
was taken some hours before breakfast than when
taken with breakfast. Bergstrom et al (17) reported
similar results. Our present report extends these observations and suggests that taking D-penicillamine 2
hours after dinner is possibly even less effective. In a
recent paper, Schuna and coworkers (36) stated that
systemic availability of penicillamine is reduced by
food, but the rate of absorption of the drug is not.
The inhibitory effect of simultaneous dosage of
iron preparations on the resorption of oral D-penicillamine is so dramatic that the low iron doses present in
geriatric and multivitamin preparations might not be
harmless in this respect. Lyle and coworkers (37)
observed that oral iron inhibits D-penicillamine-induced cupruresis, and according to Hall et a1 (38), oral
iron abolishes the D-penicillamine-induced increase in
serum thiol reactivity.
In our study, the observed decrease in Dpenicillamine resorption provides an explanation for
these results. If penicillamine disulfide is not easily
MUIJSERS ET AL
1368
resorbed, iron-catalyzed auto-oxidation of D-penicillamine may be responsible for the observed inhibitory
effect. Another possibility is that there is inhibition of
D-penicillamine resorption by formation of iron-penicillamine chelates.
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course, pharmacokinetics, level, patients, aspects, serum, penicillamine, correlation, effect, side, clinical, arthritis, rheumatoid
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