Download Plasma Concentration and Acetylator Phenotype Determine

Plasma Concentration and Acetylator Phenotype
Determine Response to Oral Hydralazine
ALEXANDER M. M. SHEPHERD, M.D.,
PH.D., JOHN L. MCNAY, M.D.
THOMAS M. LUDDEN, PH.D., MIN-SHUNG LIN,
M.D.,
AND GARY E. MUSGRAVE, PH.D.
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SUMMARY The vasodepressor response to single and multiple oral doses of hydralazine, 1 mg/kg, was
studied in hypertensive patients. The concentration of bydralazbe in plasma was measured both by a newly
developed specific and a nonspecific assay similar to those used in previous studies. Acetylator phenotype was
determined following oral sulfamethazine. Plasma hydralazine concentration peaked at 1 hour after administration and was undetectable 2 hours later. Apparent hydralazine was present in plasma in higher concentration and for a longer duration than hydralazine. The peak decreases in blood pressure (BP) were proportional to plasma hydralazine concentration following administration of both single and multiple doses and were
substantially maintained for 8 hours. In contrast there was no significant correlation between decreases in BP
and apparent hydralazine concentrations. The plasma concentration of hydralazine after a standard oral dose
varied by as much as 15-fold among individuals and was lower in rapid than slow acetylator phenotype patients.
The BP responses were positively correlated with plasma hydralazine concentrations and inversely correlated
with acetylator indices. Low plasma concentrations may account for poor responses of some patients to conventional oral doses of hydralazine. The applicability of acetylator pbenotyping for individualization of
hydralazine dosage regimens merits further evaluation. (Hypertension 3: 580-585, 1981)
KEY WORDS
blood pressure
•
acetylator phenotype
• dose response
hydralazine
H
• plasma concentration
frequent occurrence of disseminated systemic lupus
erythematosus (DSLE) in patients of fast acetylator
phenotype.11 However, there are reasons to reexamine
the status of current knowledge relating BP response
to plasma hydralazine concentration.
Most compelling is recognition that the analytic
methods used in prior studies are nonspecific, measuring a combination of hydralazine and acid labile
metabolites for which the term "apparent hydralazine" has been suggested.11 The most abundant component of apparent hydralazine is the hydralazine
pyruvic acid hydrazone (HPH),18' u which does not
reduce BP in animals."• " In addition, there is need
for a more quantitative estimate than is now available
of the extent to which interindividual differences in
plasma hydralazine concentration may account for
differences in BP response.
We have established a positive correlation between
the antihypertensive effect and the plasma concentration of hydralazine measured by a specific method.
There was no correlation between antihypertensive
effect and plasma apparent hydralazine measured by a
nonspecific method.3 In addition, we have shown that
acetylator phenotype is inversely related to hypoten-
YDRALAZINE is a drug of major importance in the treatment of hypertension.
When used in combination with a diuretic
and beta blocker, it has been shown to be effective in
patients resistant to prior therapy.1 However, examples of inadequate blood pressure (BP) responses to
regimens that include hydralazine are not infrequent.1' 8 It would be clinically useful to have a
systematic method by which patient responsiveness to
hydralazine might be predicted and dosing regimens
optimized for individual patients.
At present, empiric guidelines specify a maximum
dose of 200 mg/day/ except for fast acetylators, for
whom a maximum dose of 300 mg/day may be
used.8'" The larger recommended dose in fast
acetylators is based on the lower concentrations of
plasma hydralazine in fast acetylators relative to slow
acetylators at equivalent oral doses'"10 and the inFrom the University of Texas Health Science Center and the
Veterans Administration, San Antonio, Texas.
Address for reprints: Alexander M. M. Shepherd, M.D., Ph.D.,
Department of Pharmacology, UT Health Science Center, San Antonio, Texas 78284.
Received November 5, 1980; accepted February 26, 1981.
580
PLASMA HYDRALAZINE AND BLOOD PRESSURE/Shepherd et al.
sive response following oral administration of a standard (1 mg/kg) dose of hydralazine. The mechanism
by which the acetylator index determines the response
to hydralazine is probably related to its influence on
hydralazine bioavailability and thereby on hydralazine plasma concentration." Since the acetylator
phenotype is easy to determine, it has a marked advantage over the determination of plasma levels for
evaluation of cardiovascular responses to hydralazine.
Methods
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Nine hypertensive male patients who required
hydralazine for clinical management of essential
hypertension were admitted to the Special Diagnostic
and Treatment Unit at the Audie Murphy Veterans
Hospital (table 1). The patients had no clinical
evidence of angina pectoris, prior myocardial infarction, or cerebral vascular accident. Six days before the
study, all medications were discontinued except those
noted in table 1. Upon admission, 4 days were allowed
for acclimatization to the hospital environment. Diet
in the hospital contained 8 g of salt/day. Electrolyte
balance was not quantitated. There was no consistent
trend of body weight throughout the hospital stay.
Each patient underwent pharmacodynamic and
pharmacokinetic studies following hydralazine administration on three occasions. The three studies
were: single oral dose; single intravenous dose; and
multiple (fifth) oral dose. The multiple dose study was
conducted last in each patient due to the known persistence of BP effects after repeated doses of
hydralazine." On the fourth and eighth hospital days,
patients were given either a single oral dose of
TABLE 1. Selected Clinical Data on Hypertensive Subjects Given Single and Multiple Oral Doses of Hydralazine
Endogenous
creatinine
AcetylAge Weight clearance Concomitant ator
Patient (yr) (kg) (ml/kg/min) drug therapy index*
Hct, digoxin,
67
75
39
36
chlorprop amide
Furosemide,
57
100
92
48
digoxin,
chlorprop amide
53
50
50
55
54
63
47
87
73
90
81
116
77
80
116
45
120
70
84
57
85
Hct
Hct
Hct
Hct
Hct, allopurinol
Hct
Hct. allopurinol
18
30
65
59
72
82
70
•Acetylator index = 500 X [acetylated sulfamethazine/
total sulfamethazine] in plasma 6 hours after 10 rag/kg
sulfamethazine administered orally.
Hct = hydrochlorothiazide.
581
hydralazine, 1 mg/kg, or a single intravenous bolus of
hydralazine, 0.3 mg/kg. Following the second study,
the patients were started on a maintenance oral dose
of hydralazine, 1 mg/kg, 9:00 am and 9:00 pm. A
combination of commercial Apresoline tablet sizes
was used to approximate the maintenance dose. On
the morning of the fifth oral dose, we repeated the
study of plasma concentration and BP effects (third
study). The results of the i.v. study are reported in a
separate manuscript.
On study days, patients had nothing by mouth except water beginning the prior midnight. The patients
remained recumbent in bed without smoking throughout the study. At 7:00 am, a pediatric scalp vein needle was placed in a forearm vein for blood sampling.
The BP was measured in the arm at 10-minute intervals by an Arteriosonde. A solution of 5% dextrose
and water was slowly infused through a second intravenous needle in the other arm used for intravenous
hydralazine administration. At 9:00 am hydralazine
was administered, either orally or intravenously over a
100-second interval. The oral hydralazine dose solution was made by mixing an appropriate volume of
hydralazine for intravenous injection with 30 ml of
distilled water immediately before administration.
Blood was sampled every 5 minutes X 12, every 15
minutes X 8, and every 30 minutes until 8 hours had
elapsed. A light lunch was provided at 1 pm.
Acetylator index was determined during the
equilibration period by administration of an oral 10
mg/kg dose of sulfamethazine (Matheson, Coleman
and Bell, Norwood, Ohio). Acetylated and total sulfamethazine concentrations were measured in a
plasma sample taken 6 hours later.11 The 6-hour
plasma ratio of acetylated-to-total sulfamethazine has
been shown optimal for purposes of phenotyping.*0
The handling of blood specimens for hydralazine
analysis, which has been described elsewhere,11 was
performed in the minimum possible time. Analysis for
hydralazine and apparent hydralazine was performed
by published methodology.11'" The lower limits of
detection for the two assays were 0.0125 and 0.1
respectively.
Analysis of Data
Acetylator index was defined as the ratio, multiplied
by 100, of acetylated-to-total sulfamethazine in
plasma. Peak plasma hydralazine and apparent
hydralazine concentrations were taken as the highest
determined values. The area under the curve (AUC)
for hydralazine and for apparent hydralazine was
calculated by the trapezoid method, extrapolated to
infinity. The terminal t'/i of fast acetylator patients
was assumed to be the slope of the third and final
phase of decay from plasma after the intravenous dose
administered on a separate occasion. This provided a
maximum estimate of AUC after oral administration.17 All BP values were expressed as mean arterial
pressure (MAP), which was calculated as diastolic
pressure plus 1/3 pulse pressure.
582
HYPERTENSION
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During each of the three studies, BP was measured
12 times at 10-minute intervals prior to administration of hydralazine. Analysis of variance indicated
that the predrug BPs of the first study were not
significantly different from those of the second study,
i.e., (mean ± SE, mm Hg) 120 ± 1 and 118 ± 1 mm
Hg respectively. Since a persistent hypotensive effect
of the previous hydralazine dose was expected at the
time of the third study, predrug pressures from the
single oral study were designated as baseline for
calculation of drug effect following both the single and
fifth oral dose studies. Analysis of variance indicated
that no significant variation in MAP occurred for 2
hours prior to hydralazine administration on each of
the three study occasions. The MAP subsequent to
dose administration was calculated as the moving
average of three pressures, one before and one after
the designated time. The maximum change in MAP
(A MAP) from baseline was chosen for analysis of
drug effect.
Statistical analysis was performed by methods
specified in the text. The methods included: Student's /
for paired and unpaired data, Duncan's new multiple
range test, and multiple least squares stepwise linear
regression." Two-way analysis of variance was performed with the University of Texas Health Sciences
Center at San Antonio computer facility, using the
1977 version of BMDP 2V program."*
VOL 3, No
5, SEPTEMBER-OCTOBER
1981
TABLE 3. Mean and Range of Peak Plasma Concentrations of Apparent Hydralazine ([AH]p) and Areas under
the Plasma Concentration-Time Curves of Apparent Hydralazine (A UCAH) after the Single and Fifth Oral Doses of
Hydralazine (1 mg/kg) in Eight Hypertensive Men
Dose
sequence mean
Single
Fifth
4.8
6.6
[AH]p, nM
SE
range
0.37
1.05
3.8- 6.7
3.5-12.1
AUC AH , jiM min
mean SE
range
1260 364 435-3362
3785 2032 402-9263
not significantly different. The concentration of apparent hydralazine rose to a peak which was
11.6 ± 3.5 times that of hydralazine after the single
dose, and 25.2 ± 8 . 8 times that of hydralazine after
the fifth dose. The increase in this ratio indicated accumulation of apparent hydralazine with repetitive
dosing. Accumulation was consistent with a significant residual concentration of apparent hydralazine
(1.49 ± 0.37 nM, t test) in plasma prior to administration of the fifth dose of hydralazine. The average areas
under the plasma concentration time curves for hydralazine (AUC H ) after the single and the fifth oral doses
were strikingly small relative to the AUCs of apparent
hydralazine (AUC A H ). The average ratio of
AUC H /AUC A H following the single oral doses was
0.014 ± 0.0032. The ratio was significantly (p < 0.02,
paired t test) smaller after multiple oral doses.
Results
Plasma Concentration of Hydralazine and Apparent
Hydralazine
Blood Pressure Responses to Hydralazine: Plasma Levels
Plasma concentrations of hydralazine peaked 10 to
30 minutes after administration of either a single oral
dose or the fifth oral dose. Plasma concentrations then
decayed rapidly, becoming undetectable 60 to 180
minutes after administration. The average range of
peak plasma concentrations of hydralazine and apparent hydralazine following the single and fifth doses
are presented in tables 2 and 3. Concentrations of
hydralazine following the single and fifth dose were
TABLE 2. Mean and Range of Peak Plasma Concentrations of Hydralazine [H]p and Areas under the Plasma
Concentration-Time Curve of Hydralazine (AUCH) after
the Single and Fifth Oral Doses of Hydralazine (1 mg/kg)
in Nine Hypertensive Men
[H]p,(uM
Dose
mean
SE
range
sequence
Single
Fifth
0.62 0.23
0.51 0.17
0.11-1.3
0.10-1.4
AUC H , MM min
mean SE
range
14
15
3.3
5.0
4.0-30
3.2-41
•This program was developed at the Health Science Center computing facility, UCLA, under sponsorship of NIH Special Research
Resources Grant RR-3 from the National Institutes of Health.
The average values of MAP for 2 hours preceding
and 8 hours after oral hydralazine administration are
illustrated in figure 1. The individual peak reductions
in MAP occurred from 30 to 140 minutes after the
first oral doses and 60 to 180 minutes after the fifth
oral doses. Data for the group as a whole show there
was strong evidence of a persistent effect 10 to 12
hours following the fourth dose in the multiple oral
dose sequence. The level of baseline MAP was
significantly (p < 0.001) less preceding the fifth dose
than preceding the first dose (two-way analysis of
variance).
While the predose MAP was significantly less prior
to the fifth dose than prior to the single dose, the absolute pressure at peak effect after the fifth dose was
equal to that at peak effect after the first dose; i.e.,
there was no cumulation of peak effect on BP. In addition, recovery of MAP during the 8 hours after administration of either the single or fifth dose was not
significant (Duncan's new multiple range test).
There was a significant correlation between reductions in MAP from baseline and plasma hydralazine
concentration following both the single and fifth oral
dose (least squares regression).
These relationships are illustrated in figure 2 for
both peak hydralazine concentration and AUC H . The
ranges from lowest to highest values for peak
hydralazine plasma concentrations and AUC H were
PLASMA HYDRALAZINE AND BLOOD PRESSURE/Shepherd
583
et al.
I30-,
Single Dose
Fifth Dose
FIGURE 1. Time course of mean arterial
pressure (MA P) for 2 hours preceding and 8
hours following a single dose and the fifth of
multiple oral doses of hydralazine, administered at 12-hour intervals. All oral doses
were 1 mg/kg body weight. Results presented
as mean ± SE.
-120
-60
0
60
120 180
4 5 6 7 8
(min)
(h)
Time, Relative to Oral Administration of Hydralazine
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Single Oral Dosing
40n
Multiple Oral Dosing
AMAP= 28.0+18.2 tog[H]p
r= 0.78
p<0.0l
AMAP=24.O+I8.I log f "
p<O.OI
30-
.
10FIGURE 2. Relationships
between
peak
reduction in mean arterial pressure (MAP) and
plasma concentrations of hydralazine following a single dose (left panels) and the fifth dose
(right panels) of hydralazine, 1 mg/kg.
Hydralazine concentrations are expressed as
both peak plasma concentration (upperpanels)
and area under the plasma concentration-time
curves, A UCH (lower panels).
X
E
E
0
Ql
50
403020100
Q4 I 2
Q4 I 2
Peak H Concentration (pM)
AMAP=-|.0 + ia2log[AUC H]
r= 0.70
p<O.OI
2040
20 40
I
AUC H
40E 3020100
0
-min)
AMAP= 403-0.4 Al
r=O83 p<O.OI
A MAP= 32.1-0.3 Al
r=0.69 p<0.05
2 0 4 0 6 0
AMAP= -0.9 + 20.0 tog [AUC H]
r=0B2
p<OOI
80
100 0
20
40
60
80
100
Acetylator Index
FIGURE 3. Relationships between peak reduction in mean arterial pressure (AMAP) and acetylator index
(Al), following a single dose (left) and the fifth dose (right) of hydralazine, I mg/kg orally.
584
HYPERTENSION
approximately 15-fold. The effect/dose slopes did not
differ significantly among the four relationships.
There were no significant correlations of AMAP with
peak concentration, 2-hour concentration, or AUC of
apparent hydralazine, following either the single or
the fifth dose of hydralazine.
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Blood Pressure Response to Hydralazine: Acetylator
Pbenotype
Among the nine subjects, the acetylator index
ranged from 18 to 82 (table 1). The distribution of the
acetylator index was not bimodal but rather included
one or two patients in each decile from the second
through the ninth. There were significant (p < 0.05)
inverse relationships between AMAP and acetylator
index following both the single and the fifth oral doses
of hydralazine (figure 3).
Discussion
Our results establish a relationship between plasma
concentration of hydralazine as determined by a
specific assay and the magnitude of hypotensive effect
after oral administration of hydralazine. This correlation was significant following both single dose and the
fifth dose of a series administered at 12-hour intervals.
These data imply that a major factor accounting for
interindividual differences in the response to oral
hydralazine is the plasma concentration of the unmetabolized drug. Other factors, in particular the absolute level of pretreatment BP, may also be expected
to influence the magnitude of response (Shepherd et
al., unpublished data). There was no evidence of accumulation of hydralazine in plasma following five
doses. Likewise, the absolute BP at peak response was
the same following the single and the fifth doses.
Unlike Zacest and Koch-Weser,7 we could find no correlations between BP responses and the concentrations of apparent hydralazine. The plasma concentrations of apparent hydralazine as measured by Zacest
and Koch-Weser would be in close agreement with
those that we determined using the Jack method." We
tested possible correlations of BP response with the 2hour plasma concentration of apparent hydralazine as
well as peak concentration and AUC, since blood
sampling was performed 2 hours after dosing in
previous studies which have demonstrated relationships between BP response and plasma apparent
hydralazine concentrations.1' * Perhaps the correlation
of effect with plasma apparent hydralazine improves
with longer duration of administration, as in the
studies conducted by Zacest and Koch-Weser7 and by
Jounela et al.*
Our negative observations are consistent with the
knowledge that the Jack assay is nonspecific, measuring not only hydralazine but also acid labile hydralazine conjugates, including hydralazine pyruvic acid
hydrazone (HPH), which has been shown to constitute
the major proportion of the substances assayed by
nonspecific methods.11-" Since HPH produces no
VOL 3, No 5, SEPTEMBER-OCTOBER
1981
hypotensive effect in the rabbit," rat (Clementi, unpublished data), and dog,18 it presumably does not
contribute to the hypotensive effect of administered
hydralazine in the human. Inclusion of a large and
variable proportion of HPH in the nonspecific assay
results is ample basis for the absence of a good correlation of plasma concentration with antihypertensive effect.
A principal factor accounting for interindividual
differences in hydralazine concentration after a standard oral dose is acetylator phenotype. It was
recognized by Zacest et al.,1 Reidenberg et al.,' and
Talseth10 that the concentrations of apparent
hydralazine after oral administration were lower in
fast acetylators than in slow acetylators. In addition,
we have established an inverse correlation between
acetylator index and both the peak plasma concentration of hydralazine and the AUC H ." It seems most
probable that the inverse relationship of acetylator index to BP response is due to the former's effect on
bioavailability and therefore the plasma concentration of hydralazine at the doses we studied. There is
the additional possibility that acetylator index influences the response to hydralazine through a pharmacodynamic mechanism in addition to the
postulated pharmacokinetic mechanism (Shepherd et
al, unpublished data).
The distribution of acetylator index among our
patients was consistent with recent kinetic studies that
have shown a trimodal, rather than bimodal, population distribution." On the basis of our results, we
think that there is an advantage to expressing acetylation capacity as the absolute value of the acetylator index rather than dichotomously as slow and fast.
The data imply that, for patients with a high
acetylator index, the dose of hydralazine required for
a substantial vasodepressor response may be quite
large, i.e., up to 15 times as large as the dose required
for an equivalent effect in the slowest acetylators.
Taking a 30 mm Hg vasodepressor response as an example, and the range of acetylator index observed in
our group of patients, we estimate the doses would be
2 mg/kg/day for a patient with the lowest acetylator
index and 30 mg/kg/day for a patient with the highest
acetylator index. Since a dose of 4 mg/kg/day is the
current upper limit of the recommended dosage range
for hydralazine, the most rapid acetylators would be
expected to develop approximately one third of the
desired responses to hydralazine. This must be considered a possible factor in the poor response to hydralazine seen in some patients.8- 8 That plasma concentration of hydralazine may not be the only factor in
refractoriness to hydralazine is suggested by the
failure of some patients who were designated as
"slow" acetylators to respond to daily doses of 200 to
400 mg." We propose that it is necessary to measure
the plasma hydralazine concentration to conclusively
establish clinical refractoriness to hydralazine. Alternatively, measurement of acetylator index may
provide a clinically adequate estimate of plasma hydralazine concentration relative to oral dose. In addition, compliance must be unequivocally established.
PLASMA HYDRALAZINE AND BLOOD PRESSURE/Shepherd et al.
We conclude that patients with a high acetylator index need a greater than 50% increment in the now
recommended maximum daily dose of 200 mg if they
are to have plasma concentrations of hydralazine that
would produce a substantial antihypertensive effect.
The practical usefulness of acetylator index in predicting the dose of hydralazine required to produce a
desired vasodepressor response remains to be established. If acetylator index should provide a
guideline of this type, potentially unresponsive
patients could be spared the time and expense of an
unsuccessful therapeutic trial of hydralazine. Alternatively, doses larger than 300 mg/day might be given
patients with a high acetylator index if the toxicity of
hydralazine, like its efficacy, is related to its plasma
concentration.
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References
1. Zacest R, Gilmore E, Koch-Weser J: Treatment of essential
hypertension with combined vasodilation and bcta-adrcnergic
blockade. N Engl J Med 286: 617, 1972
2. Gottlieb TB, Katz FH, Chidsey CA III: Combined therapy
with vasodilator drugs and beta-adrenergic blockade in hypertension. Circulation 45: 571, 1972
3. Pettinger WA, Mitchell HC: Minoxidil — an alternative to
nephrectomy for refractory hypertension. N Engl J Med 289:
167, 1973
4. Committee on Hypertension: Drug treatment of ambulatory
patients with hypertension. JAMA 225: 1647, 1973
5. Koch-Weser J: Hydralazine. N Engl J Med 295: 320, 1976
6. Editorial. Hydrallazine. Lancet 1: 342, 1977
7. Zacest R, Koch-Weser J: Relation of hydralazine plasma concentration to dosage and hypotensive action. Clin Pharmacol
Ther 13: 420, 1972
8. Reidenberg MM, Drayer D, DeMarco AL, Bello CT:
Hydralazine elimination in man. Clin Pharmacol Ther 14:970,
1973
9. Jounela AJ, Pasanen M, Mattila MJ: Acetylator phenotype
and the antihypertensive response to hydralazine. Act a Med
Scand 197: 303, 1975
10. Talseth T: Studies on hydralazine. I. Serum concentrations of
hydralazine in man after a single dose and at steady state. Eur J
Clin Pharmacol 10: 183, 1976
585
11. Perry HM Jr: Late toxicity to hydralazine resembling systemic
lupus erythematosus or rheumatoid arthritis. Am J Med 54:58,
1973
12. Zak SB, Lukas G, Gilleran TG: Plasma levels of renal and "apparent" hydralazine in man and rat. Drug Metab Dispos 5:116,
1977
13. Recce PA, Stanley PE, Zacest R: Interference in assays for
hydralazine in humans by a major plasma metabolite, hydralazine pyruvic acid hydrazone. J Pharm Sci 67: 1150, 1978
14. Shepherd AMM, Ludden TM, Haegele KD, Talseth T, McNay
JL: Pharmacokinetics of hydralazine, apparent hydralazine and
hydralazine pyruvic acid hydrazone in humans. Res Commun
Chem Pathol Pharmacol 26: 129, 1979
15. Talseth T, Haegele KD, McNay JL, Skrdlant HB, Clementi
WA, Shepherd AMM: Pharmacokinetics and cardiovascular
effects in rabbits of a major plasma metabolite, the hydralazine
pyruvic acid hydrazone. J Pharm Exp Ther 211: 509, 1979
16. Shepherd AMM, Musgrave GE, Badke F, Walsh" R: Tachycardia associated with hydralazine pyruvic acid hydrazone, the
major plasma metabolite of hydralazine. Fed Proc 39: 1190,
1980
17. Shepherd AMM, Ludden TM, McNay JL, Lin M-S: Pharmacokinetics of hydralazine after administration of single and
multiple oral doses. Clin Pharm Ther. In press
18. O'Malley K, Segal JL, Israili ZN, Boles M, McNay JL,
Dayton PG: Duration of hydralazine action in hypertension.
Clin Pharm Ther 18: 581, 1975
19. Olson W, Miceli J, Weber W: Dose-dependent changes in sulfamcthazine kinetics in rapid and slow isoniazid acetylators.
Clin Pharmacol Ther 23: 204, 1978
20. du Souich P, McLean AJ, Stoechel K, Ohlendorf D, Gibaldi M:
Screening methods uiing sulfamethazine for determining
acetylator phenotype. Clin Pharmacol Ther 26: 757, 1979
21. Ludden TM, Goggin LK, McNay JL, Haegele KD, Shepherd
AMM: High pressure liquid chromatographic assay for hydralazine in human plasma. J Pharm Sci 68: 1423, 1979
22. Jack DB, Brechbdhler S, Dagen PH, Zbinden P, Reiss W: The
determination of hydralazine in plasma by gas-liquid chromatography. J Chromatogr 115: 87, 1975
23. Steel RGD, Torrie JH: Principles and Procedures of Statistics.
New York: McGraw-Hill, 1960
24. Jenrich R, Sampson P: Analysis of variance and variance including repeated measures, program revised December 21,
1977. Chap 15.2. In BMDP Biomedical Computer Programs,
P-Series, 1979, edited by Dixon WJ, Brown MB. Berkley:
University of California Press, 1977
25. Chapron DJ, Kramer PA, Mercik SA: Kinetic discrimination
of 3 sulfamethazine phenotypes. Clin Pharmacol Ther 27: 104,
1980
26. Hunyor SN: Hydrallazine and beta-blockade in refractory
hypertension with characterization of acetylator phenotype.
Aust N Z J Med 5: 530, 1975
Plasma concentration and acetylator phenotype determine response to oral hydralazine.
A M Shepherd, J L McNay, T M Ludden, M S Lin and G E Musgrave
Hypertension. 1981;3:580-585
doi: 10.1161/01.HYP.3.5.580
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