Studies of Plasma Quinidine Content
I. Relation to Single Dose Administration by Three Routes
By RICHARD W. KALMANSOHN, M.D., AND JOHN J. SAMPSON, M.D.
The plasma quinidine curves obtained by the oral and intramuscular routes of administration
of 0.6 Gm. quinidine sulfate and 0.65 Gm. quinidine lactate, respectively, were generally similar.
Maximal concentration, averaging 3.2 mg. per liter in the former group occurred from one-half
hour to four hours after administration, and in the latter averaged 2.6 mg. per liter in one to three
hours. Significant quantity of quinidine remained at eight hours, and small amounts at twentyfour hours. Rectal administration of 0.6 Gm. quinidine sulfate resulted in lower concentrations,
the maximum averaging 0.89 mg. per liter. The chief value of intramuscular quinidine therapy
appears to be the avoidance of gastrointestinal irritation, but hypotensive reactions were relatively frequent in the small series of patients studied.
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1) showed maximum plasma quinidine contents varying from 2.9 to 3.7 mg. per liter with
an average content of 3.2 mg.; these peak concentrations occurred from one-half to four and
one-quarter hours after administration of the
drug, or in an average time of two and onequarter hours. The fall in plasma content of
quinidine (table 2) occurred at about the following rates: 55 to 96 per cent of the maximum
concentration remained in four hours, 42 to 73
per cent remained in eight hours, and 0 to 22
per cent was still present in twenty-four hours.
The above findings are approximately the
same as those observed by other investigators.
Wegria and Boyle1 gave 4 patients 0.8 Gm.
and 2 patients 0.6 Gm. of quinidine sulfate
orally and observed maximum plasma concentrations ranging from approximately 2.0 to
3.0 mg. per liter in from one to four hours.
Delevett and Poindexter2 administered 1.0 Gm.
of quinidine to 20 patients and noted maximum
concentrations varying from 1.48 to 4.32 mg.
per liter in from three-quarters to four hours.
Hiatt3 gave 10.0 mg. of quinidine per kilogram
of body weight (approximately 0.70 Gm. to a
patient weighing 150 pounds) and recorded
maximum concentrations of from 2.0 to 3.0
mg. per liter in two to three hours in several
patients. Linenthal, Ulick, and Patterson4
noted average maximum quinidine concentrations of 2.0 mg. per liter occurring in from one
to three hours after doses of 0.6 Gm. of quinidine were administered. Though the quinidine
SEVERAL groups of workers have reported the plasma quinidine concentrations after the oral administration of
single doses of quinidine sulfate.'-4 In the present study, quinidine sulfate was given orally
and rectally and quinidine lactate intramuscularly, and the pattern of quinidine concentration was determined at various times after
administration.
The plasma quinidine content was determined by the fluorometric method described
by Brodie and Udenfriend in 1943.5 The procedure consists of adding a fixed volume of
metaphosphoric acid to a diluted plasma specimen to obtain a protein-free filtrate, and then
of determining the concentration of quinidine
in the filtrate by means of a photofluorometer.
The patients (table 1) were chosen at random, but with care to exclude anyone with
gastrointestinal or urinary tract disturbances.
Plasma samples were obtained prior to the administration of the quinidine and at regular
intervals thereafter, usually according to the
following schedule: at fifteen, thirty, and sixty
minutes, and at two, four, eight, twelve, and
twenty-four hours.
The observations in 6 patients using single
oral doses of 0.6 Gm. of quinidine sulfate (fig.
Frcm the Department of Medicine and Harold
Brunn Institute for Cardiovascular Research, Mount
Zion Hospital, San Francisco, Calif.
Read before the Western Society for Clinical Research, October 23, 1948, Los Angeles, Calif.
564
TABLE 1.-Plasma Quinidine Concentrations in Subjects with Sinus Rhythm after the Administration of Single
Doses by Oral, Rectal, or Intramuscular Routes
Age
,1(years)
Sex
Case
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
M
M
F
M
M
F
M
F
M
M
F
F
F
M
F
M
1-MB
2-AD
3-GG
4-RS
5-MM
6-AY
7-EG
8-KC
9-WR
10-MG
11-ST
12-JM
13-RH
27-JG
28-MA
33-KM
Height Weight
(feetinches) (pounds)
65
43
26
64
63
59
73
66
65
78
59
70
67
27
59
51
5-5
5-8
5-6
5-7
5-2
5-5
5-0
5-6
5-61
5-0
Dose
(gram)
5-1
5-6
5-4
2
3.1
2.9
3.4
3.7
3.0
3.36
1.1
0.51
0.75
1.19
0.43
0.85
1.76
3.45
3.20
2.34
0.6 orally
0.6 orally
0.6 orally
0.6 orally
0.6 orally
0.6 orally
0.6 rectally
0.6 rectally
0.6 rectally
0.6 rectally
0.13 IM
0.13 IM
0.65 IM
0.65 IM
0.65 IM
0.65 IM
145
125
125
170
155
132
155
140
128
95
135
88
106
179
5-12
Time Required
for Maximum
Maximum Concentration
Level
to
be Reached
(mg./
after AdminisLiter) tration
of Quinidine (hours)
Number of
Hours Quinidine Still
Detected in
Plasma
24
13
18
24
24
24
8
11
12
12
1
2
412
11
2
11
21
32
2
31:
6
12
61
3
4
.312
11
24
212
1
24
24
24
2 23
3
4 1
Quinidine Plosma Level
Quinidine Plosma Level
Mg/Liter
Mg /Liter
3
3
3
>
|
~~~~~~Quipidine Suifote
~~~M.B. 0.6 gm. Orolly
_
5
Quinidine Sulfate
M.M. 0.6gm. Orally
2
2
0
OA
v
s
0o
5
20
z5
5
5
0
25
20
Hours
Hours
4
R.S.
Quinidine Sulfate
0. 6 gm. Orolly
3
3
2
Quinidine Sulfate
A.D. 0.6gm. Orally
2
a
O
15
20
15
10
20
25
4
4
3
Quinidirne Sulfate
|G. 0.6
3
gm. . Orally
6
A.Y.
Quinidine Sulfote
0.6gm. Orally
2
0
n
5
10
15
20
25
Fie. 1.-Plasma quinidine concentration curves following the administration
0.60 Cm. of quinidine sulfate orally to each of six patients.
565
of
single
doses of
566
STUDIES OF PLASMA QUINIDINE CONTENT
concentrations fluctuated among individuals,
the average concentrations did not show much
variation when dosages of from 0.6 to 1.0 Gm.
were given in the above groups of cases.
Six patients were given quinidine lactate,*
intramuscularly. Five of these are illustrated
in figure 2. Of this group, 2 patients received
0.13 Gm. and showed maximum plasma contents of 0.85 and 0.43 mg. per liter in three and
three-quarters and three-quarters hours, respecTABLE 2.-Fall in Concentration of Plasma Quinidine
after Administration of the Drug by Three Different
Routes Expressed in Approximate Percentage of
the Mlaximum Levels Reached at Various Times
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Case
8 Hours
Max. Conc. 4 Hours
Reached in After Ad- After AdFollowing ministration ministration
Hours
(Per Cent) |(Per Cent)
24 Hours
After Administration
(Per Cent)
Intramuscularly
13-RH
27-JG
28-MA
21
71
1
33-KEM
3
94
93
83
223
45
64
75
83
10
20
25
28
73
42
47
55
45
52
22
0.0
9.0
4.0
2.7
Orally
1-MB
2-AD
3-GG
4-RS
5-MM
6-AY
96
2
85
42
12
l'
12
*
87
55
312
12.0
Rectally
7-EG
8-KC
9-WR
10-MG
92
2
32
6
*
12
67
61
66
80
40
0.0
0.0
0.0
0.0
Maximum concentrations occurred after the
four-hour determination.
*
tively. Four patients received 0.65 Gm. each
and the maximum plasma contents varied from
1.76 to 3.45 mg. per liter with an average of
2.68 milligrams. The peaks occurred in an average of two and one-third hours with a range
of from one to three hours; this is similar to
the peak concentrations obtained in those pa*Quinidine lactate
Eli Lill, and Co.
was
generously
supplied bh-
tients who received quinidine orally. The percentage fall from maximum concentrations
(table 2) was less than for the orally administered quinidine; 71 to 94 per cent remained at
four hours, 45 to 83 per cent at eight, and 10
to 28 per cent at twenty-four hours. Assuming
that these figures are significant, it is possible
that the delav in excretion could be due to
fixation of quinidine by skeletal muscle, which
has been demonstrated by Wegria and Boylet
to fix about one-third to one-half the quantity
of quinidine fixed by cardiac muscle. There was
more variation of the maximum quinidine
plasma concentrations among those receiving
the drug intramuscularly than among those
receiving it orally.
In 4 patients who were given 0.6 Gm. of
quinidine sulfate rectally (fig. 3), the maximum
plasma quinidine contents varied from 0.51 to
1.19 mg. per liter, an average of 0.89 mg., with
peaks at one and one-half to six hours in an
average time of three and one-quarter hours.
About 40 to 80 per cent of the maximum concentration was present in eight hours, only a
trace remained at twelve hours, and none was
detected at twenty-four hours after the time
of administration (table 2).
There was no consistent correlation between
the weights of patients and the plasma quinidine concentrations.
SUMMARY AND CONCLUSIONS
1. The plasma quinidine concentrations observed when the drug was given by three
routes, orally, intramuscularly, and rectally,
were compared. The maximum concentrations
following the administration by the three routes
of approximately 0.60 Gm. of quinidine averaged, respectively, 3.2, 2.68, and 0.89 mg. per
liter in an average time of two and one-quarter,
two and one-third, and three and one-quarter
hours.
2. The intramuscular route, resulting in approximately the same plasma concentration
curves as when the drug is given by the oral
route, would seem to be valuable chiefly when
quinidine cannot be given orally because of certain patients' intolerance to the oral administration as evidenced by nausea or diarrhea and
567
RICHARD W. KALMANSOHN AND JOHN J. SAMPSON
Ouinidine Plusmo Levels
Mg/ Liter
4
28
0.65 gm. Quintdine Lactate
M. A.
liM
Quinidine Plasma Levels
Mg/ Liter
2
13
0.65gm. Quinidine Lactote IM
R.H.
1~~~~~~~1.4
Ephedrine gr.3/4
0
0
5
5
Hours
8 p 135 9510
toso so
50
80
10
20
15
25
125
P14011014o
Ts-o- -ro
135
s
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2
0.13gm. Quinidine Lactate IM
12
3
J. M.
2
5
10
I5
25
20
0.13gm. Ouinidine Loctate IM
11
S.T.
0
0
5
10
15
25
20
5
BP 125
us
Hours
ItO
132
5
es
14e
to
FIG. 2.-Plasma quinidine concentration curves following the administration of single doses of
quinidine lactate, 0.6 or 0.13 Gm. intramuscularly, to each of five patients.
Quinidine Plsma Love I
Mg/ L iter
2
21
|
0
I
0.6gm. Quinidine Sulfote
10
M.G.
5
10
Quinidine Plasma Level
Mg/ Liter
8
K.C.
Rectolly
15
20
25
01
5
o10
0.6 gm. Quinidine Sulfote
Rectally
15
20
25
Hours
Hours
2
2
7
0.6 gm. Quinidine S ulf ote
E.G. Rectolly
9
W. R.
0
0. 6 gm. Quinidine Sulf ate
Rectally
n
V,*
5
10
15
20
25
5
10
15
20
25
FIG. 3.-Plasma quinidine concentration curves following the administration of 0.60 Gm. of quinidine sulfate rectally to each of four patients.
'568
STUDIES OF PLASMA QUINIDINE CONTENT
wvhen nausea and vomiting preclude any oral
medication. Quinidine can be administered rectally, but dosages probably two to three times
those used orally may be necessary to obtain
equivalent plasma concentrations.
REFERENCES
1
2
R.,YAND BOYLE, N.N.: CorIelation
between the effect of quininine sulfate on the
heart and its concentration in the 10loo0( pllasma.
Am. J. __Med. 3: 373, 1948.
DELEVETT, A. F., AND POINDEXTER, C. A.: Plasima
concentrations of quinidine with J)articular refer-
WEGRIA,
ence
cases
to therapeutically effective levels in two
of l)aroxysmal
no(al
tachycardia. AmI.
Heart J. 32: 697, 1946.
3HIATT, Il P.: Plasma concentrations following
the oral administration of single (loses of the
principal alkaloids of cinchona bark. J. Plharmnacol. & Eixper. Tlherap. 81: 160, 1944.
4LINENTHAL, A. J., ULICK, S., AND PATrrERSON,
L. A.: Fluorometric measure of
p)lasma quinidine.
J. Cliti. Investigation 26: 1188, 1947.
BRODIE, B. B., AND IUDE'NFRIEND, S.: The estimiation of quinine inhu1 1 lasm Witlh note on
the estimation of quinicline. J. Pharmacol. &
Expce. Therap. 78: 154, 1943.
an
a
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Studies of Plasma Quinidine Content: I. Relation to Single Dose Administration by Three
Routes
RICHARD W. KALMANSOHN and JOHN J. SAMPSON
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Circulation. 1950;1:564-568
doi: 10.1161/01.CIR.1.4.564
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