Patterns of plasma concentrations and urinary excretion of salicylate in rheumatoid arthritis lntersubject differences in the volume of distribution, whole body clearance, and steady-state plasma concentrations of salicylic acid (SA) were studied in a series of patients with rheumatoid arthritis and healthy control subjects. The measurement of the plasma concentration of SA 12 hr after an oral dose of 1.2 gm aspirin appears predictive of the success of long-term dosage of aspirin. Concentrations below 5 /J-g/ml in this single-dose test were associated with failure to achieve therapeutic plasma concentrations of SA (above 150 /J-g/ml) during long-term therapy with approximately 4.8 gm aspirin per day. Conversely, plasma concentrations above 10 /J-g/ml in the single-dose test were associated with levels above 150 /J-g/ml during long-term therapy. The volume of distribution of SA correlated poorly with body weight (r = 0.51, P < 0.01) and did not correlate significantly with plasma albumin levels. Corticosteroids appear to induce the metabolism of SA and most subjects dosed with oral corticosteroids and aspirin 4.8 gm/day did not attain plasma levels of SA above 150 /J-g/ml. The clearance of SA was greater in male than in female patients. The difference appears to be of clinical significance since fewer men than women achieved therapeutic plasma concentrations of SA.
G. G. Graham, G. D. Champion, R. O. Day, and P. D. Paull Sydney, Australia Departments of Clinical Pharmacology and Rheumatology, St. Vincent's Hospital
One of the problems of the use of aspirin and other salicylates is the wide range of plasma concentrations attained. For example, daily dosage of aspirin, 65 mg/kg body weight, yielded plasma concentrations of salicylate (SA) ranging from 50 to 290 ILg/ml,l5 While there has been no formal study relating suppression of inflammation to the plasma concentrations of SA, considerable clinical evidence indicates that plasma concentrations above 150 ILg/ml are usually required for clinically Received for publication Sept. 22, 1976. Accepted for publication April 29, 1977. Reprint requests to: G. G. Graham, Department of Clinical Pharmacology, St. Vincent's Hospital, Darlinghurst, N.S.W. 2010. Australia.
410
significant anti-inflammatory activity. 8 Many patients receiving total daily doses up to approximately 4.8 gm aspirin do not attain therapeutic plasma concentrations of SA. Clearly, higher concentrations could be attained by increasing the dose of aspirin, but this may not be feasible because of gastric irritation and problems with the compliance of patients and thus daily doses of aspirin rarely exceed 4.8 gm per day. We have surveyed the pharmacokinetics of SA in healthy subjects and in patients with rheumatoid arthritis. The aim was to determine some of the factors responsible for the considerable intersubject differences in plasma concentrations of SA during the long-term adminis-
Volume 22 Number 4
Salicylate kinetics in rheumatoid arthritis 411
tration of aspirin, in particular the factors responsible for the subtherapeutic concentrations of SA in some subjects. In the course of the studies, it became apparent that a single-dose test may enable the selection of those subjects who should attain therapeutic plasma concentrations of SA during therapy with total daily doses of approximately 4.8 gm aspirin. This potential single-dose test was evaluated in some detail.
tered at total daily doses of approximately 4.8 gm, as shown in Table II. Formulations used were soluble tablets (as above) or enteric-coated tablets (Rhusal) containing 650 mg aspirin. A previous study showed good bioavailability of aspirin from this formulation. 3 Subjects taking the soluble tablets also received a simultaneous dose of 8 ml of antacid, each milliliter containing 4 mg simethicone, 40 mg magnesium hydroxide, and 40 mg aluminum hydroxide (Mylanta). At least 4 days passed between the commencement of therapy and the collection of blood or 24-hr urine specimens. Blood samples were taken 2 hr after the second dose of the day. Assay methods. The concentrations of SA in plasma were assayed by slight modifications of the automated method of Hill and SmithS or by the manual method of Rowland and Riegelman. l6 The concentration of total SA in urine was assayed by the method of Levy and ProcknaP2 after hydrolysis in an equal volume of 10 N hydrochloric acid and autoclaving for 2 hr at 120 0 C. Free SA was assayed by the procedure of Levy and Procknal. 12 Albumin was assayed by the method of Bartholomew and Delaney.2 Kinetic parameters. The volume of distribution (V d) of SA was estimated by two procedures as shown in Equations I and 2:
Methods
Selection of subjects. Two groups were studied: patients with rheumatoid arthritis and control subjects. Details of subjects are given in Table I. Patients with rheumatoid arthritis. The study began with Patients S. G. and M. C. who were studied because of inadequate therapeutic response to high daily doses of aspirin. The remainder were consecutive hospitalized patients for whom salicylate therapy was considered appropriate. All received high daily doses of aspirin (Table II) either before or after the single-dose study. No patient received aspirin for at least 3 days prior to the single-dose study. Control subjects. Healthy subjects were selected as controls for the patients with rheumatoid arthritis according to age and weight. Four of the control subjects were orthopedic patients. The control subjects remained supine for at least 8 hr in order to simulate the activity of the patients with rheumatoid arthritis. Single-dose study. Two hours after a light breakfast (toast and beverage), the subjects received 4 x 300-mg soluble aspirin tablets (Solcetas), dissolved in approximately 200 ml water. Times for blood samples were set at 0,0.5, 1, 2.5, 5, 8, and 12 hr after dosage and times for urine samples were set at the following times after dosage: 0, 1, 2.5, 3.5, 5, 6.5, 8, 10, and 12 hr and at 4-hr intervals for the following 12 hr. However, not all samples could be collected from the hospitalized patients at the exact times specified. Blood was collected with the use of edathamil as the anticoagulant. Both urine and plasma were stored at - 20 0 C until assayed. Multiple-dose study. Aspirin was adminis-
Vd =
:rCpdt - tfCpdt
D
:rCpdt
CPt
o. -
(1)
where CPt = concentrations of SA in plasma at t hr after dosage (JLg/ml) and D = dose of aspirin calculated as JLg SA. Ab t = D-A t Vd=--
CPt
CPt
(2)
where Ab t = amount of SA in the body at t hr after dosage and At = amount of total SA recovered in urine up to t hr after dosage. In cases in which the collection times of the corresponding plasma and urine samples differed by more than 3 min, CPt values were estimated by 3- or 4-point Lagrangian interpolation. The half-life (t;6) of SA was recorded as the time taken for plasma concentrations to decrease from maximal to half concentrations, the
412
Graham et al.
Clinical Pharmacology and Therapeutics
Table I. Details of subjects
Age
Weight (kg)
Plasma albumin (gm/JOO ml)
M
53
85
3.7
Rheumatoid arthritis
Supine
R.H.
M
34
73
4.2
Rheumatoid arthritis
Sitting
G.A.
M
42
103
4.2
Rheumatoid arthritis
Sitting
R. B.
M
48
64
4
Sitting
R. P.
M
66
53
4.4
S. G.'
M
20
76
3.4
N.M.
F
44
50
3.5
Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis
M.C.
F
56
65
3.7
S. C.
F
30
55
3.8
R. Pi.
M
43
85
4.2
L. Q.
M
54
63.5
4
O.O'S. M
51
59
3.8
C.T.
M
51
81
4
L. H.
M
48
64
3.6
Patient
Sex
O.W.
Condition
Activity
Corticosteroids (daily dose)
Supine
Prednisone (12.5 mg), methylprednisolone IA (40 mg on day of single dose Prednisone (10 mg) methylprednisolone IA (80 mg) 2 days before single-dose test Prednisone (10-15 mg), methylprednisolone IA during multipledose test Methylprednisolone IA (60 mg) 2 days before single-dose test Methylprednisolone IA (80 mg) 3 days before single-dose test Prednisone (25 mg)
Supine
Betamethasone (0.75 mg)
Rheumatoid arthritis
Ambulant
Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Inflammatory arthritis Rheumatoid arthritis (?)
Ambulant
Prednisone, 5 mg during single-dose test and 10 mg during multipledose study Prednisone (5 mg)
time of half maximal concentration again being estimated by 3- or 4-point Lagrangian interpolation. Whole body clearance (CI) was calculated from the quotient Cpdt. Statistics. The significance of differences in kinetic parameters in the various groups was evaluated by unpaired t test.
Df:I
Results
Single-dose studies have now been conducted in 25 subjects with rheumatoid arthritis and in 8 age-matched control subjects. The plasma level profiles varied widely in the sub-
Sitting
Ambulant Supine Sitting Supine
Methylprednisolone IA during multiple-dose study Methylprednisolone IA during multiple-dose study Methylprednisolone IA during multiple-dose study
Supine
jects and representative plasma level data are shown in Fig. 1. Intersubject differences in the plasma concentrations of SA were particularly marked at 12 hr after dosage and the value of this single 12-hr value (Cp12) has been evaluated as a guide to aspirin dosage and to intersubject differences in the pharmacokinetics of SA. Two factors appeared to be associated with high Cl of SA in the patients with rheumatoid arthritis. The values of Cl were higher in male than in female subjects. Further, the oral administration of corticosteroids was associated with higher Cl in both male and female patients (Ta-
Salicylate kinetics in rheumatoid arthritis 413
Volume 22 Number 4
100
Other medication Other drugs Indomethacin, nitrazepam Diazepam, ferrous sulfate, methandienone, desipramine Phenylbutazone, paracetamol, diazepam, codeine, pentobarbital Diazepam, indomethacin, ibuprofen, antacid Nitrazepam, diazepam, indomethacin, aurothiomalate Ferrous sulfate, potasium chloride paracetamol Paracetamol, dextropropoxyphene, pentazocine, codeine Paracetamol, dextropropoxyphene, indomethacin
80
~ ~
60
()
i;;:
:::;
~
~
8
g~
Nitrazepam, dextropropoxyphene, paracetamol, antacid Chlorambucil, calcium hydroxychloroquine, antacid, nitrazepam
Dextropropoxyphene, aurothiomalate Pentobarbital, pethidine
Indomethacin, hydroxychloroquine Alcohol, diazepam Ibuprofen, dioctyl sodium sulfosuccinate, insulin Paracetamol, dextropropoxyphene Nitrazepam, paracetamol, auroth iomal ate , antacid Indomethacin, tetracycline, antacid
i 0
Danthron, antacid, nitrazepam Antacid, nitrazepam
bles II and III). Similar differences were noted with values of t~ and CP12, although they were not significant (Table III). Similar trends associated with the administration of corticosteroids and the sex of the patients were noted in the plasma concentration of SA (Cpss) during long-term therapy with aspirin, although the effect of steroids was significant only in female patients and the sex difference was significant only in patients who were not taking steroids (Tables II and III). Low Cpss values in men were very marked, and of the 14 male patients surveyed Cpss values
40 20
2
4
6
8
10
12
TIME, hours
Fig. 1. Time-course of plasma concentrations of SA following dosage of 1.2 gm aspirin to 2 subjects with rheumatoid arthritis. Plasma concentrations of SA observed during long-term therapy with aspirin were 97 f.Lg/ml (Me) and 285 f.Lg/ml (DH).
above 150 JLg/ml were achieved in only 3, whereas in 9 of the 11 female patients the Cpss values were above 150 JLg/ml. (In 2 of the female patients, Cpss values were above 350 JLg/ml and the dosage of aspirin was reduced to 3.6 gm/day.) Some patients received intra-articular injections of methylprednisolone either just before the single dose or during the long-term administration of aspirin, but the number of patients given intra-articular methylprednisolone was too small for statistical analysis. Data from these patients was excluded from the statistical analysis described above. There were no significant differences in the kinetic parameters of SA in the healthy male and female subjects. The clearance of SA was lower in the male control subjects than in the male patients with rheumatoid arthritis (p < 0.05). The clearance of SA was very rapid in one of the female subjects (D. J.), and the difference in the clearance of SA in the female control subjects and the female patients not given corticosteroids approached significance (0.1 > P > 0.05). A correlation was observed between Cpss and CP12 values (r = 0.83, P < 0.001; Fig. 2). A negative correlation was also noted between Cpss and CI (r = -0.78, P < 0.001) while a poorer, though significant, correlation was also noted between Cpss and t~ (r = 0.48,
414
Graham et al.
Clinical Pharmacology and Therapeutics
Table I. Cont'd
Age
Weight (kg)
Plasma albumin (gml100 ml)
M
13
48
4.6
E. V.
M
57
71
4.7
F. L.
M
56
73
W.F.
M
52
76
Patient
Sex
D. O.
~
Condition
Activity
Rheumatoid arthritis Rheumatoid arthritis
Ambulant
Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis
Ambulant
Sitting
Sitting
D. R.
F
16
44
4.8
D.H.
F
59
65
3.8
H.M.
F
54
78
4.8
N. K.
F
51
52
4.2
Rheumatoid arthritis
Ambulant
W.1.
F
58
78
3.6
Rheumatoid arthritis
Sitting
L. R.
F
60
50
4.0
Sitting
L. O.
F
18
52
4.8
M.O.
F
57
47
4.1
J. B.
M M M M M F
52
64
N. S. O. O. W.C. D.Oo. D.J.
4.7 5.1 5.1 5 4.8 4.3
Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Healthy Orthopedic Healthy Healthy Healthy Orthopedic
C.M.
F
24
4.6
Orthopedic
Supine
G. Gri. F
56
4.3
Orthopedic
Supine
33
37 36 19 28
70 76 76 66 58
65
Corticosteroids (daily dose)
Methylprednisolone lA during multiple-dose study
Sitting Supine Ambulant
Methylprednisolone IA during multiple-dose study
Methylprednisolone IA during multiple-dose study
Sitting Sitting Supine Supine Supine Ambulant Supine Supine
IA: Intra-articular.
p < 0.05). It should be emphasized that these correlation coefficients were calculated from the results in all subjects, although there was a small range in the daily dosage of aspirin (4.55 to 5.2 gm/day). CP12 values of 5 J-Lg/ml or less were observed in 10 patients. In 9 of these patients, levels of
SA failed to reach 150 J-Lg/ml during therapy with approximately 4.8 gm aspirin per day. One subject, R. P., with Cp12 below 5 J-Lg/ml, did reach a Cps. above 150 J-Lg/ml. This subject, however, was dosed with the highest dosage regime of aspirin, 5.2 gm/day. Furthermore, this subject received an intra-articular injection
Salicylate kinetics in rheumatoid arthritis 415
Volume 22 Number 4
400
•
•
Other medication 300
Other drugs
Diazepam, dextropropoxyphene, paracetamol Penicillin V, indomethacin, paracetamol Aurothiomalate Antacid, diazepam, nitrazepam, aurothiomalate Aurothiomalate, dextropropoxyphene, paracetamol Indomethacin Furosemide, ibuprofen, paracetamol, dextropropoxyphene Potassium chloride, paracetamol, amitriptyline, thyroxine, conjugated estrogens, thioridazine, antacid Furosemide, paracetamol, nitrazepam, potassium chloride Nitrazepam
20
Antacid ~g/ml
Aurothiomalate, nitrazepam, dextropropoxyphene
:
.
•
..J_--r I
•
I
---
• I I
I I I
10
Nitrazepam, prochlorperazine Antacid, ferrous sulfate Furosemide, nitrazepam, ibuprofen, dextropropoxyphene
Antacid
Indomethacin Aurothiomalate, ferrous sulfate, hexamine None Cloxacillin, ampicillin None None None Penicillin V, ampicillin, paracetamol Dextropropoxyphene, paracetamol, pentazocine, calcium gluconate Nitrazepam, dextropropoxyphene, paracetamol
cP ....
Potassium chloride, ibuprofen, nitrazepam
Dextropropoxyphene, nitrazepam Pentobarbital, danthron, ferrous sulfate, lactulose
of methylprednisolone acetate 3 days prior to the single-dose study but received no corticosteroid during the long-term study. Cp12 values above 10 J,Lg/ml were generally associated with Cpss values above 150 J,Lg/ml. The most marked exception was Subject D. G. who differed from all others examined in the
20
30
40
CPI2·lIII/ml
Fig. 2. Correlation between plasma concentrations of SA during long-term therapy with aspirin (CpsS> and plasma concentrations of SA 12 hr after a single dose of 1.2 gm aspirin (Cpu) (r = 0.83, p < 0.001). Broken lines at Cp12 of 5 and 10 p,g/ml and Cpss of 150 p,g/ml. large amount of unconjugated SA excreted. (Table II). In all other subjects tested, unconjugated SA accounted for less than 15% of the total SA excretion in both the single- and multiple-dose studies. Estimates of the V d of SA are shown in Table II. Computation of V d by both methods assumes that absorption is complete at the time of sampling. This assumption appeared reasonable in view of the rapid absorption of aspirin. In most cases, maximal levels were observed 1 hr after dosing, with similar values 0.5 hr after dosage (Fig. 1). Absorption was slow in 2 subjects (S. G. and L. G.) and maximal SA levels were observed at 2.5 hr, while data up to 1 hr after dosage was used to compute V d in all other subjects. More reliance was placed on the calculation of V d by the method involving area analysis, but the urinary procedure provided a useful check of the values of V d. In those subjects in whom V d was measured by both methods, the mean Vd calculated by the method involving urinary analysis was 11.9 L and 11.0 L when determined by area analysis. The difference is small but statistically highly significant (p < 0.001). Values of Vd calculated by area analysis have been used in all subsequent correlations and discussion. The values of Vd ranged from 7.9 to 17.9 L and correlated poorly with the body weight of
416
Clinical Pharmacology and Therapeutics
Graham et al.
Table II. Kinetic data, plasma levels, and urinary excretion of salicylate Aspirin dosage during longterm study
Vd (L) Patient
t1,l2 (hr)
From areaJ From urinary analysis excretion
Cl
CP ss Cp12 (/J-g/ml) (/J-g/ml) ----------
(Gmil day)
Dose form
Percent excreted as salicylate
I
Single Multiple dose dose
-----
Male.patients with rheumatoid arthritis-concurrent steroids O.W. 2.9 14 55.4 1.2 13.6 R. H. 4.1 12.9 15.2 46.6 1.6 G. A. 3.8 12.8 2.2 14.0 45.5 4.6 R. B.* 9.5 3.2 10.4 33.5 R. P.* 4.1 3.7 9.8 9.8 34.4 S. G. 4.7 13.6 16.0 40.6 5.0 Mean 2.5 3.9 13.2 47.0 ±SE ±0.4 ±0.2 ±3.1 ±0.8
67 90 124 120 162 58 85 ±15
4.8 4.8 4.8 4.8 5.2 4.8
Soluble Soluble Soluble Soluble Enteric Soluble
Female patients with rheumatoid arthritis-concurrent steroids N.M. 3.1 8.2 9.7 35.9 1 M.C. 3.2 8.1 8.7 33.7 3.3 S. C. 5.3 28.8 10.8 10.0 8.4 Mean 3.9 9.0 32.8 4.2 ±SE ±0.7 ±0.9 ±2.1 ±2.2
97 97 241 145 ±48
4.55 4.8 4.55
Enteric Soluble Enteric
Male patients with rheumatoid arthritis-no concurrent steroids in single-dose study 4.0 R. Pi. 11.9 12.8 44.5 4.8 97 1.3 Soluble L. Q.t 3.1 10.8 15.2 42.5 4.8 2.2 130 Soluble D.O'St 4.4 9.7 11.0 30.7 5.2 160 4.8 Soluble C. T. 5.4 17.9 4.8 84 38.6 8.5 Soluble 14.2 L. H. 6.7 32.3 11.1 D.G. 6.4 10.8 11.7 26.0 12.6 129 4.8 Soluble E. V. 13.6 5.2 5.4 13.5 28.6 15.0 148 Enteric 4.8 F. L. 17.1 224 Soluble 4.8 W. F.t 80 Soluble Mean 5.1 12.7 34.7 9.1 132 ±0.5 ±1.1 ±SE ±2.7 ±2.1 ±17
4.1
0.3
2.2 11.4 4.2 4.6 2.2
14.6 10.0
0.7 12.9 10.1 9.4 32 2.5 8.3
'Patients receiving intra-articular injections of methylprednisolone within 3 days of single-dose study. Results from these subjects not included in computation of mean data. tPatients receiving intra-articular injections of methylprednisolone during multiple-dose study. Values of Cp" deleted from computation of mean data.
the subjects, although the correlation was significant with the number of subjects studied (Fig. 3). There was no significant correlation between Vd and the concentration of albumin in plasma. There was no significant influence of the administration of corticosteroids on Vd and the mean Vd (± standard deviation) in all subjects was 11.2 ± 2.3 L and the relative Vd was 0.167 ± 0.030 L/kg. Significant, although poor, correlations were observed between Cpss and Vd (r = -0.47, P < 0.05) and between Cl and Vd (r = 0.54, p < 0.01). Discussion
Examination of intersubject differences in the pharmacokinetics of SA is difficult because of
the saturable kinetics of the drug. Calculation of Vd presents several difficulties. Calculation of Vd by the area analysis method assumes that elimination of SA is eliminated by first-order processes. It is well known that SA is eliminated by parallel first- and zero-order processes 13 but, only a small fraction of the dose is eliminated in the first hour so that the error in the use of this method of area analysis was probably small. Calculations of V d by the urinary excretion procedure is valid irrespective of the order of elimination 14 but is accurate only if the elimination of metabolites is extremely rapid compared with the rate of formation. The t% of the major metabolite of SA, salicylurate, is approximately
Volume 22 Number 4
Salicylate kinetics in rheumatoid arthritis 417
Table II. Cont'd
Vd (L) Patient
tY2 (hr)
I
From area From urinary analysis excretion
Cl
CP ss Cp12 ( JLglml) ( JLglml)
Female patients with rheumatoid arthritis-no concurrent steroids D. R. 10.5 D. H. 12.1 5.8 10.7 27.9 11.6 10.6 11.2 23.8 15.3 H. M.t 6.2 N. K. 20.4 17.9 5.8 8.2 W. J. 11.9 21.9 21.4 6.5 10.4 L. R. 23.0 L. G. 4.5 7.9 9.0 17.2 24.8 M.G. 37.4 Mean 9.6 22.2 5.8 20.2 ±SE ±0.3 ±0.6 ±1.8 ±3.l Male control subjects J. B. 5.0 11.7 N. S. 6.1 11.9 G. G. 5.0 11.8 W.C. 5.2 9.7 D. Go. 5.8 9.8 Mean 5.4 11.0 ±SE ±0.2 ±0.5 Female control subjects D. J. 14.2 3.9 C. M. 4.5 9.4 G. Gri. 6.5 11.3 Mean 5 11.6 ±SE ±0.8 ±1.4
11.4 12.3 11.9 10.1 10.5
30.7 28.9 27.0 22.0 20.6 25.8 ±2.0
10.9 12.1 14.4 19.2 20.2 15.4 ±1.9
15.1 9.7
57.3 30.9 25.9 38.0 ±9.7
2.1 5.8 15.0 7.6 ±3.8
15 min,10 which can be compared with the initial SA tY2 which ranged from 2.9 to 6.7 hr (Table II). Consequently, there should have been a slight accumulation of salicylurate. According to Equation 2, the small lag in the elimination of salicylurate should have caused a small overestimate of Ab t and hence a slight overestimate of V d. A more significant problem with this procedure was the frequent necessity to estimate the plasma concentration of SA at the time of the collection of urine, since urine and plasma samples were often collected at significantly different times; furthermore, any incomplete urine collections will increase the value of Vd calculated by this method. Considering the errors in the two methods, calculation of V d by the area method appeared the more accurate and was consequently used in the various statistical analyses. Calculated values of Cl and tY2 will not be
Aspirin dosage during longterm study
Percent excreted as salicylate
1
Single Multiple dose dose
(Gm1 day)
Dose form
in single-dose study Enteric 258 5.2 Enteric 285 5.2 Soluble 223 4.8 215 Soluble 4.8 254 4.55 Enteric 213 4.8 Soluble Soluble 379 4.8 Soluble 380 4.8 276 ±24
ii!
fi5
14.7 6.5
1.3
• •
14
•
12
15
~ g
7.6
•
18
~
I
• 10
.: 40
. 80 BODY
•
•
80 WEIGHT (Kg)
100
Fig. 3. Relationship between Vd of SA and body weight (r = 0.51, P < 0.01). constant because of the saturable kinetics of SA. Values of Cl will decrease and value of tlh will increase after the accumulation of large amounts of SA during the long-term therapy of high doses of aspirin. The values of tlh and
418
Graham et al.
Clinical Pharmacology and Therapeutics
Table III. Probability values for contrast of kinetic data and plasma concentrations in subjects with rheumatoid arthritis p values (unpaired t test) Contrast
Males (concurrent steroids)-females (concurrent steroids) Males (concurrent steroids)-males (no steroids) Females (concurrent steroids)-females (no steroids) Males (no steroids)-fema1es (no steroids)
Cl calculated after one dose of aspirin should however be reasonable indicators of intersubject differences in the pharmacokinetics of SA during long-term dosage with aspirin. This hypothesis is supported by the significant correlations between Cpss and tV2 and between Cpss and Cl. The influence of corticosteroids on the elimination of SA is of particular interest since corticosteroids are frequently administered with aspirin to patients with severe rheumatoid arthritis. Corticosteroids appear to decrease the steady-state levels of SA during the long-term administration of aspirin. 7 From their clearance studies, Klinenberg and Miller 7 concluded that steroids increased the renal clearance of SA, but their assay procedures did not distinguish between SA and salicylurate. From the more specific assays used in the present study, little SA was excreted unconjugated. Consequently, corticosteroids must induce the metabolism of SA rather than its urinary excretion. Insufficient patients receiving intra-articular injections of methylprednisolone were included in the present study to identify any effect these injections on the pharmacokinetics of SA. While these injections exhibit some systemic effects for at least 3 days, 9 direct observations of the kinetics of SA metabolism before and after intra-articular injections of corticosteroids are required to demonstrate directly any influence of such injections on the metabolism of SA. lt was of note that only one subject tested (D. G.) excreted a significant proportion of total SA as unconjugated SA when dosed with antacid and aspirin. Therapeutic levels of SA in the multiple-dose study were not achieved in this patient, possibly as a result of the excretion of
Cl
G. G. Graham, G. D. Champion, R. O. Day, and P. D. Paull Sydney, Australia Departments of Clinical Pharmacology and Rheumatology, St. Vincent's Hospital
One of the problems of the use of aspirin and other salicylates is the wide range of plasma concentrations attained. For example, daily dosage of aspirin, 65 mg/kg body weight, yielded plasma concentrations of salicylate (SA) ranging from 50 to 290 ILg/ml,l5 While there has been no formal study relating suppression of inflammation to the plasma concentrations of SA, considerable clinical evidence indicates that plasma concentrations above 150 ILg/ml are usually required for clinically Received for publication Sept. 22, 1976. Accepted for publication April 29, 1977. Reprint requests to: G. G. Graham, Department of Clinical Pharmacology, St. Vincent's Hospital, Darlinghurst, N.S.W. 2010. Australia.
410
significant anti-inflammatory activity. 8 Many patients receiving total daily doses up to approximately 4.8 gm aspirin do not attain therapeutic plasma concentrations of SA. Clearly, higher concentrations could be attained by increasing the dose of aspirin, but this may not be feasible because of gastric irritation and problems with the compliance of patients and thus daily doses of aspirin rarely exceed 4.8 gm per day. We have surveyed the pharmacokinetics of SA in healthy subjects and in patients with rheumatoid arthritis. The aim was to determine some of the factors responsible for the considerable intersubject differences in plasma concentrations of SA during the long-term adminis-
Volume 22 Number 4
Salicylate kinetics in rheumatoid arthritis 411
tration of aspirin, in particular the factors responsible for the subtherapeutic concentrations of SA in some subjects. In the course of the studies, it became apparent that a single-dose test may enable the selection of those subjects who should attain therapeutic plasma concentrations of SA during therapy with total daily doses of approximately 4.8 gm aspirin. This potential single-dose test was evaluated in some detail.
tered at total daily doses of approximately 4.8 gm, as shown in Table II. Formulations used were soluble tablets (as above) or enteric-coated tablets (Rhusal) containing 650 mg aspirin. A previous study showed good bioavailability of aspirin from this formulation. 3 Subjects taking the soluble tablets also received a simultaneous dose of 8 ml of antacid, each milliliter containing 4 mg simethicone, 40 mg magnesium hydroxide, and 40 mg aluminum hydroxide (Mylanta). At least 4 days passed between the commencement of therapy and the collection of blood or 24-hr urine specimens. Blood samples were taken 2 hr after the second dose of the day. Assay methods. The concentrations of SA in plasma were assayed by slight modifications of the automated method of Hill and SmithS or by the manual method of Rowland and Riegelman. l6 The concentration of total SA in urine was assayed by the method of Levy and ProcknaP2 after hydrolysis in an equal volume of 10 N hydrochloric acid and autoclaving for 2 hr at 120 0 C. Free SA was assayed by the procedure of Levy and Procknal. 12 Albumin was assayed by the method of Bartholomew and Delaney.2 Kinetic parameters. The volume of distribution (V d) of SA was estimated by two procedures as shown in Equations I and 2:
Methods
Selection of subjects. Two groups were studied: patients with rheumatoid arthritis and control subjects. Details of subjects are given in Table I. Patients with rheumatoid arthritis. The study began with Patients S. G. and M. C. who were studied because of inadequate therapeutic response to high daily doses of aspirin. The remainder were consecutive hospitalized patients for whom salicylate therapy was considered appropriate. All received high daily doses of aspirin (Table II) either before or after the single-dose study. No patient received aspirin for at least 3 days prior to the single-dose study. Control subjects. Healthy subjects were selected as controls for the patients with rheumatoid arthritis according to age and weight. Four of the control subjects were orthopedic patients. The control subjects remained supine for at least 8 hr in order to simulate the activity of the patients with rheumatoid arthritis. Single-dose study. Two hours after a light breakfast (toast and beverage), the subjects received 4 x 300-mg soluble aspirin tablets (Solcetas), dissolved in approximately 200 ml water. Times for blood samples were set at 0,0.5, 1, 2.5, 5, 8, and 12 hr after dosage and times for urine samples were set at the following times after dosage: 0, 1, 2.5, 3.5, 5, 6.5, 8, 10, and 12 hr and at 4-hr intervals for the following 12 hr. However, not all samples could be collected from the hospitalized patients at the exact times specified. Blood was collected with the use of edathamil as the anticoagulant. Both urine and plasma were stored at - 20 0 C until assayed. Multiple-dose study. Aspirin was adminis-
Vd =
:rCpdt - tfCpdt
D
:rCpdt
CPt
o. -
(1)
where CPt = concentrations of SA in plasma at t hr after dosage (JLg/ml) and D = dose of aspirin calculated as JLg SA. Ab t = D-A t Vd=--
CPt
CPt
(2)
where Ab t = amount of SA in the body at t hr after dosage and At = amount of total SA recovered in urine up to t hr after dosage. In cases in which the collection times of the corresponding plasma and urine samples differed by more than 3 min, CPt values were estimated by 3- or 4-point Lagrangian interpolation. The half-life (t;6) of SA was recorded as the time taken for plasma concentrations to decrease from maximal to half concentrations, the
412
Graham et al.
Clinical Pharmacology and Therapeutics
Table I. Details of subjects
Age
Weight (kg)
Plasma albumin (gm/JOO ml)
M
53
85
3.7
Rheumatoid arthritis
Supine
R.H.
M
34
73
4.2
Rheumatoid arthritis
Sitting
G.A.
M
42
103
4.2
Rheumatoid arthritis
Sitting
R. B.
M
48
64
4
Sitting
R. P.
M
66
53
4.4
S. G.'
M
20
76
3.4
N.M.
F
44
50
3.5
Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis
M.C.
F
56
65
3.7
S. C.
F
30
55
3.8
R. Pi.
M
43
85
4.2
L. Q.
M
54
63.5
4
O.O'S. M
51
59
3.8
C.T.
M
51
81
4
L. H.
M
48
64
3.6
Patient
Sex
O.W.
Condition
Activity
Corticosteroids (daily dose)
Supine
Prednisone (12.5 mg), methylprednisolone IA (40 mg on day of single dose Prednisone (10 mg) methylprednisolone IA (80 mg) 2 days before single-dose test Prednisone (10-15 mg), methylprednisolone IA during multipledose test Methylprednisolone IA (60 mg) 2 days before single-dose test Methylprednisolone IA (80 mg) 3 days before single-dose test Prednisone (25 mg)
Supine
Betamethasone (0.75 mg)
Rheumatoid arthritis
Ambulant
Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Inflammatory arthritis Rheumatoid arthritis (?)
Ambulant
Prednisone, 5 mg during single-dose test and 10 mg during multipledose study Prednisone (5 mg)
time of half maximal concentration again being estimated by 3- or 4-point Lagrangian interpolation. Whole body clearance (CI) was calculated from the quotient Cpdt. Statistics. The significance of differences in kinetic parameters in the various groups was evaluated by unpaired t test.
Df:I
Results
Single-dose studies have now been conducted in 25 subjects with rheumatoid arthritis and in 8 age-matched control subjects. The plasma level profiles varied widely in the sub-
Sitting
Ambulant Supine Sitting Supine
Methylprednisolone IA during multiple-dose study Methylprednisolone IA during multiple-dose study Methylprednisolone IA during multiple-dose study
Supine
jects and representative plasma level data are shown in Fig. 1. Intersubject differences in the plasma concentrations of SA were particularly marked at 12 hr after dosage and the value of this single 12-hr value (Cp12) has been evaluated as a guide to aspirin dosage and to intersubject differences in the pharmacokinetics of SA. Two factors appeared to be associated with high Cl of SA in the patients with rheumatoid arthritis. The values of Cl were higher in male than in female subjects. Further, the oral administration of corticosteroids was associated with higher Cl in both male and female patients (Ta-
Salicylate kinetics in rheumatoid arthritis 413
Volume 22 Number 4
100
Other medication Other drugs Indomethacin, nitrazepam Diazepam, ferrous sulfate, methandienone, desipramine Phenylbutazone, paracetamol, diazepam, codeine, pentobarbital Diazepam, indomethacin, ibuprofen, antacid Nitrazepam, diazepam, indomethacin, aurothiomalate Ferrous sulfate, potasium chloride paracetamol Paracetamol, dextropropoxyphene, pentazocine, codeine Paracetamol, dextropropoxyphene, indomethacin
80
~ ~
60
()
i;;:
:::;
~
~
8
g~
Nitrazepam, dextropropoxyphene, paracetamol, antacid Chlorambucil, calcium hydroxychloroquine, antacid, nitrazepam
Dextropropoxyphene, aurothiomalate Pentobarbital, pethidine
Indomethacin, hydroxychloroquine Alcohol, diazepam Ibuprofen, dioctyl sodium sulfosuccinate, insulin Paracetamol, dextropropoxyphene Nitrazepam, paracetamol, auroth iomal ate , antacid Indomethacin, tetracycline, antacid
i 0
Danthron, antacid, nitrazepam Antacid, nitrazepam
bles II and III). Similar differences were noted with values of t~ and CP12, although they were not significant (Table III). Similar trends associated with the administration of corticosteroids and the sex of the patients were noted in the plasma concentration of SA (Cpss) during long-term therapy with aspirin, although the effect of steroids was significant only in female patients and the sex difference was significant only in patients who were not taking steroids (Tables II and III). Low Cpss values in men were very marked, and of the 14 male patients surveyed Cpss values
40 20
2
4
6
8
10
12
TIME, hours
Fig. 1. Time-course of plasma concentrations of SA following dosage of 1.2 gm aspirin to 2 subjects with rheumatoid arthritis. Plasma concentrations of SA observed during long-term therapy with aspirin were 97 f.Lg/ml (Me) and 285 f.Lg/ml (DH).
above 150 JLg/ml were achieved in only 3, whereas in 9 of the 11 female patients the Cpss values were above 150 JLg/ml. (In 2 of the female patients, Cpss values were above 350 JLg/ml and the dosage of aspirin was reduced to 3.6 gm/day.) Some patients received intra-articular injections of methylprednisolone either just before the single dose or during the long-term administration of aspirin, but the number of patients given intra-articular methylprednisolone was too small for statistical analysis. Data from these patients was excluded from the statistical analysis described above. There were no significant differences in the kinetic parameters of SA in the healthy male and female subjects. The clearance of SA was lower in the male control subjects than in the male patients with rheumatoid arthritis (p < 0.05). The clearance of SA was very rapid in one of the female subjects (D. J.), and the difference in the clearance of SA in the female control subjects and the female patients not given corticosteroids approached significance (0.1 > P > 0.05). A correlation was observed between Cpss and CP12 values (r = 0.83, P < 0.001; Fig. 2). A negative correlation was also noted between Cpss and CI (r = -0.78, P < 0.001) while a poorer, though significant, correlation was also noted between Cpss and t~ (r = 0.48,
414
Graham et al.
Clinical Pharmacology and Therapeutics
Table I. Cont'd
Age
Weight (kg)
Plasma albumin (gml100 ml)
M
13
48
4.6
E. V.
M
57
71
4.7
F. L.
M
56
73
W.F.
M
52
76
Patient
Sex
D. O.
~
Condition
Activity
Rheumatoid arthritis Rheumatoid arthritis
Ambulant
Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis
Ambulant
Sitting
Sitting
D. R.
F
16
44
4.8
D.H.
F
59
65
3.8
H.M.
F
54
78
4.8
N. K.
F
51
52
4.2
Rheumatoid arthritis
Ambulant
W.1.
F
58
78
3.6
Rheumatoid arthritis
Sitting
L. R.
F
60
50
4.0
Sitting
L. O.
F
18
52
4.8
M.O.
F
57
47
4.1
J. B.
M M M M M F
52
64
N. S. O. O. W.C. D.Oo. D.J.
4.7 5.1 5.1 5 4.8 4.3
Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis Healthy Orthopedic Healthy Healthy Healthy Orthopedic
C.M.
F
24
4.6
Orthopedic
Supine
G. Gri. F
56
4.3
Orthopedic
Supine
33
37 36 19 28
70 76 76 66 58
65
Corticosteroids (daily dose)
Methylprednisolone lA during multiple-dose study
Sitting Supine Ambulant
Methylprednisolone IA during multiple-dose study
Methylprednisolone IA during multiple-dose study
Sitting Sitting Supine Supine Supine Ambulant Supine Supine
IA: Intra-articular.
p < 0.05). It should be emphasized that these correlation coefficients were calculated from the results in all subjects, although there was a small range in the daily dosage of aspirin (4.55 to 5.2 gm/day). CP12 values of 5 J-Lg/ml or less were observed in 10 patients. In 9 of these patients, levels of
SA failed to reach 150 J-Lg/ml during therapy with approximately 4.8 gm aspirin per day. One subject, R. P., with Cp12 below 5 J-Lg/ml, did reach a Cps. above 150 J-Lg/ml. This subject, however, was dosed with the highest dosage regime of aspirin, 5.2 gm/day. Furthermore, this subject received an intra-articular injection
Salicylate kinetics in rheumatoid arthritis 415
Volume 22 Number 4
400
•
•
Other medication 300
Other drugs
Diazepam, dextropropoxyphene, paracetamol Penicillin V, indomethacin, paracetamol Aurothiomalate Antacid, diazepam, nitrazepam, aurothiomalate Aurothiomalate, dextropropoxyphene, paracetamol Indomethacin Furosemide, ibuprofen, paracetamol, dextropropoxyphene Potassium chloride, paracetamol, amitriptyline, thyroxine, conjugated estrogens, thioridazine, antacid Furosemide, paracetamol, nitrazepam, potassium chloride Nitrazepam
20
Antacid ~g/ml
Aurothiomalate, nitrazepam, dextropropoxyphene
:
.
•
..J_--r I
•
I
---
• I I
I I I
10
Nitrazepam, prochlorperazine Antacid, ferrous sulfate Furosemide, nitrazepam, ibuprofen, dextropropoxyphene
Antacid
Indomethacin Aurothiomalate, ferrous sulfate, hexamine None Cloxacillin, ampicillin None None None Penicillin V, ampicillin, paracetamol Dextropropoxyphene, paracetamol, pentazocine, calcium gluconate Nitrazepam, dextropropoxyphene, paracetamol
cP ....
Potassium chloride, ibuprofen, nitrazepam
Dextropropoxyphene, nitrazepam Pentobarbital, danthron, ferrous sulfate, lactulose
of methylprednisolone acetate 3 days prior to the single-dose study but received no corticosteroid during the long-term study. Cp12 values above 10 J,Lg/ml were generally associated with Cpss values above 150 J,Lg/ml. The most marked exception was Subject D. G. who differed from all others examined in the
20
30
40
CPI2·lIII/ml
Fig. 2. Correlation between plasma concentrations of SA during long-term therapy with aspirin (CpsS> and plasma concentrations of SA 12 hr after a single dose of 1.2 gm aspirin (Cpu) (r = 0.83, p < 0.001). Broken lines at Cp12 of 5 and 10 p,g/ml and Cpss of 150 p,g/ml. large amount of unconjugated SA excreted. (Table II). In all other subjects tested, unconjugated SA accounted for less than 15% of the total SA excretion in both the single- and multiple-dose studies. Estimates of the V d of SA are shown in Table II. Computation of V d by both methods assumes that absorption is complete at the time of sampling. This assumption appeared reasonable in view of the rapid absorption of aspirin. In most cases, maximal levels were observed 1 hr after dosing, with similar values 0.5 hr after dosage (Fig. 1). Absorption was slow in 2 subjects (S. G. and L. G.) and maximal SA levels were observed at 2.5 hr, while data up to 1 hr after dosage was used to compute V d in all other subjects. More reliance was placed on the calculation of V d by the method involving area analysis, but the urinary procedure provided a useful check of the values of V d. In those subjects in whom V d was measured by both methods, the mean Vd calculated by the method involving urinary analysis was 11.9 L and 11.0 L when determined by area analysis. The difference is small but statistically highly significant (p < 0.001). Values of Vd calculated by area analysis have been used in all subsequent correlations and discussion. The values of Vd ranged from 7.9 to 17.9 L and correlated poorly with the body weight of
416
Clinical Pharmacology and Therapeutics
Graham et al.
Table II. Kinetic data, plasma levels, and urinary excretion of salicylate Aspirin dosage during longterm study
Vd (L) Patient
t1,l2 (hr)
From areaJ From urinary analysis excretion
Cl
CP ss Cp12 (/J-g/ml) (/J-g/ml) ----------
(Gmil day)
Dose form
Percent excreted as salicylate
I
Single Multiple dose dose
-----
Male.patients with rheumatoid arthritis-concurrent steroids O.W. 2.9 14 55.4 1.2 13.6 R. H. 4.1 12.9 15.2 46.6 1.6 G. A. 3.8 12.8 2.2 14.0 45.5 4.6 R. B.* 9.5 3.2 10.4 33.5 R. P.* 4.1 3.7 9.8 9.8 34.4 S. G. 4.7 13.6 16.0 40.6 5.0 Mean 2.5 3.9 13.2 47.0 ±SE ±0.4 ±0.2 ±3.1 ±0.8
67 90 124 120 162 58 85 ±15
4.8 4.8 4.8 4.8 5.2 4.8
Soluble Soluble Soluble Soluble Enteric Soluble
Female patients with rheumatoid arthritis-concurrent steroids N.M. 3.1 8.2 9.7 35.9 1 M.C. 3.2 8.1 8.7 33.7 3.3 S. C. 5.3 28.8 10.8 10.0 8.4 Mean 3.9 9.0 32.8 4.2 ±SE ±0.7 ±0.9 ±2.1 ±2.2
97 97 241 145 ±48
4.55 4.8 4.55
Enteric Soluble Enteric
Male patients with rheumatoid arthritis-no concurrent steroids in single-dose study 4.0 R. Pi. 11.9 12.8 44.5 4.8 97 1.3 Soluble L. Q.t 3.1 10.8 15.2 42.5 4.8 2.2 130 Soluble D.O'St 4.4 9.7 11.0 30.7 5.2 160 4.8 Soluble C. T. 5.4 17.9 4.8 84 38.6 8.5 Soluble 14.2 L. H. 6.7 32.3 11.1 D.G. 6.4 10.8 11.7 26.0 12.6 129 4.8 Soluble E. V. 13.6 5.2 5.4 13.5 28.6 15.0 148 Enteric 4.8 F. L. 17.1 224 Soluble 4.8 W. F.t 80 Soluble Mean 5.1 12.7 34.7 9.1 132 ±0.5 ±1.1 ±SE ±2.7 ±2.1 ±17
4.1
0.3
2.2 11.4 4.2 4.6 2.2
14.6 10.0
0.7 12.9 10.1 9.4 32 2.5 8.3
'Patients receiving intra-articular injections of methylprednisolone within 3 days of single-dose study. Results from these subjects not included in computation of mean data. tPatients receiving intra-articular injections of methylprednisolone during multiple-dose study. Values of Cp" deleted from computation of mean data.
the subjects, although the correlation was significant with the number of subjects studied (Fig. 3). There was no significant correlation between Vd and the concentration of albumin in plasma. There was no significant influence of the administration of corticosteroids on Vd and the mean Vd (± standard deviation) in all subjects was 11.2 ± 2.3 L and the relative Vd was 0.167 ± 0.030 L/kg. Significant, although poor, correlations were observed between Cpss and Vd (r = -0.47, P < 0.05) and between Cl and Vd (r = 0.54, p < 0.01). Discussion
Examination of intersubject differences in the pharmacokinetics of SA is difficult because of
the saturable kinetics of the drug. Calculation of Vd presents several difficulties. Calculation of Vd by the area analysis method assumes that elimination of SA is eliminated by first-order processes. It is well known that SA is eliminated by parallel first- and zero-order processes 13 but, only a small fraction of the dose is eliminated in the first hour so that the error in the use of this method of area analysis was probably small. Calculations of V d by the urinary excretion procedure is valid irrespective of the order of elimination 14 but is accurate only if the elimination of metabolites is extremely rapid compared with the rate of formation. The t% of the major metabolite of SA, salicylurate, is approximately
Volume 22 Number 4
Salicylate kinetics in rheumatoid arthritis 417
Table II. Cont'd
Vd (L) Patient
tY2 (hr)
I
From area From urinary analysis excretion
Cl
CP ss Cp12 ( JLglml) ( JLglml)
Female patients with rheumatoid arthritis-no concurrent steroids D. R. 10.5 D. H. 12.1 5.8 10.7 27.9 11.6 10.6 11.2 23.8 15.3 H. M.t 6.2 N. K. 20.4 17.9 5.8 8.2 W. J. 11.9 21.9 21.4 6.5 10.4 L. R. 23.0 L. G. 4.5 7.9 9.0 17.2 24.8 M.G. 37.4 Mean 9.6 22.2 5.8 20.2 ±SE ±0.3 ±0.6 ±1.8 ±3.l Male control subjects J. B. 5.0 11.7 N. S. 6.1 11.9 G. G. 5.0 11.8 W.C. 5.2 9.7 D. Go. 5.8 9.8 Mean 5.4 11.0 ±SE ±0.2 ±0.5 Female control subjects D. J. 14.2 3.9 C. M. 4.5 9.4 G. Gri. 6.5 11.3 Mean 5 11.6 ±SE ±0.8 ±1.4
11.4 12.3 11.9 10.1 10.5
30.7 28.9 27.0 22.0 20.6 25.8 ±2.0
10.9 12.1 14.4 19.2 20.2 15.4 ±1.9
15.1 9.7
57.3 30.9 25.9 38.0 ±9.7
2.1 5.8 15.0 7.6 ±3.8
15 min,10 which can be compared with the initial SA tY2 which ranged from 2.9 to 6.7 hr (Table II). Consequently, there should have been a slight accumulation of salicylurate. According to Equation 2, the small lag in the elimination of salicylurate should have caused a small overestimate of Ab t and hence a slight overestimate of V d. A more significant problem with this procedure was the frequent necessity to estimate the plasma concentration of SA at the time of the collection of urine, since urine and plasma samples were often collected at significantly different times; furthermore, any incomplete urine collections will increase the value of Vd calculated by this method. Considering the errors in the two methods, calculation of V d by the area method appeared the more accurate and was consequently used in the various statistical analyses. Calculated values of Cl and tY2 will not be
Aspirin dosage during longterm study
Percent excreted as salicylate
1
Single Multiple dose dose
(Gm1 day)
Dose form
in single-dose study Enteric 258 5.2 Enteric 285 5.2 Soluble 223 4.8 215 Soluble 4.8 254 4.55 Enteric 213 4.8 Soluble Soluble 379 4.8 Soluble 380 4.8 276 ±24
ii!
fi5
14.7 6.5
1.3
• •
14
•
12
15
~ g
7.6
•
18
~
I
• 10
.: 40
. 80 BODY
•
•
80 WEIGHT (Kg)
100
Fig. 3. Relationship between Vd of SA and body weight (r = 0.51, P < 0.01). constant because of the saturable kinetics of SA. Values of Cl will decrease and value of tlh will increase after the accumulation of large amounts of SA during the long-term therapy of high doses of aspirin. The values of tlh and
418
Graham et al.
Clinical Pharmacology and Therapeutics
Table III. Probability values for contrast of kinetic data and plasma concentrations in subjects with rheumatoid arthritis p values (unpaired t test) Contrast
Males (concurrent steroids)-females (concurrent steroids) Males (concurrent steroids)-males (no steroids) Females (concurrent steroids)-females (no steroids) Males (no steroids)-fema1es (no steroids)
Cl calculated after one dose of aspirin should however be reasonable indicators of intersubject differences in the pharmacokinetics of SA during long-term dosage with aspirin. This hypothesis is supported by the significant correlations between Cpss and tV2 and between Cpss and Cl. The influence of corticosteroids on the elimination of SA is of particular interest since corticosteroids are frequently administered with aspirin to patients with severe rheumatoid arthritis. Corticosteroids appear to decrease the steady-state levels of SA during the long-term administration of aspirin. 7 From their clearance studies, Klinenberg and Miller 7 concluded that steroids increased the renal clearance of SA, but their assay procedures did not distinguish between SA and salicylurate. From the more specific assays used in the present study, little SA was excreted unconjugated. Consequently, corticosteroids must induce the metabolism of SA rather than its urinary excretion. Insufficient patients receiving intra-articular injections of methylprednisolone were included in the present study to identify any effect these injections on the pharmacokinetics of SA. While these injections exhibit some systemic effects for at least 3 days, 9 direct observations of the kinetics of SA metabolism before and after intra-articular injections of corticosteroids are required to demonstrate directly any influence of such injections on the metabolism of SA. lt was of note that only one subject tested (D. G.) excreted a significant proportion of total SA as unconjugated SA when dosed with antacid and aspirin. Therapeutic levels of SA in the multiple-dose study were not achieved in this patient, possibly as a result of the excretion of
Cl
