Psychopharmacology (1997) 129 : 265-270
9 Springer-Verlag 1997
Kotra Ajir 9 M i c h a e l S m i t h 9 K e h - M i n g Lin J o s e p h C. Fleishaker - J a m e s H . C h a m b e r s D o r a A n d e r s o n 9 I n o c e n c i a N u c c i o 9 Yanping Z h e n g Russell E. Poland
The pharmacokineticsand pharmacodynamicsof adinazolam: multi-ethnic comparisons Received: 19 June 1996/Final version: 17 September 1996
Abstract The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD), its major active metabolite, were compared in 39 healthy male volunteers (13 Asian, 12 Caucasian and 14 African-American). In a four-way, double-blind crossover design; subjects were administered (1) 30 mg oral adinazolam mesylate SR tablets, (2) 10mg parenteral (IV) adinazolam mesylate, (3) 30 mg IV NDMAD and (4) placebo. Venous blood samples were collected at specific time intervals after drug administration and assayed for adinazolam and N D M A D concentrations. Sedation was rated at the time of each blood draw according to the Nurse-Rated Sedation Scale, and the digit-symbol substitution test was administered to evaluate psychomotor performance. After IV administration of adinazolam, Asians manifested significantly higher Cm~x, larger AUC and lower CL of both adinazolam and N D M A D than their Caucasian and African-American counterparts. Likewise, after IV N D M A D Asians had significantly higher N D M A D Cmax and AUC than Caucasians and AfricanAmericans. Most of these differences remained statistically significant after controlling for body surface area. With PO adinazolam, Asians also manifested substantially higher Cmax, larger AUC and lower CL for both adinazolam and N D M A D ; however, with the
Supported in part by N I M H Research Center on the Psychobiology of Ethnicity MH47193, N I M H Research Scientist Development Award MH00534 (R. E. Poland), Pharmacia and Upjohn Inc., and NIC G C R C grant MO1 RR00425 K. Ajir " M. Smith ( [ ] ) 9 K.-M. Lin ' D. Anderson I. Nuccio 9 Y. Zheng - R.E. Poland Department of Psychiatry and the Research Center on the Psychobiology of Ethnicity, Harbor-UCLA Medical Center, 1124 West Carson Street, B-4 South, Torrance, CA 90502, USA Tel (+ 1)310/222-4266, FAX (+ 1)310/222-4264, e-mail:
[email protected] J.C. Fleishaker 9 J.H. Chambers Clinical Pharmacokinetics Unit, Pharmacia & Upjohn Inc,, 7000 Portaue Road, Kalamazoo, MI 49001-0199, USA
exception of Cmax, these differences did not reach statistical significance. These results are in accordance with previous observations for ethnic-related differences in drug pharmacokinetics. In contrast, pharmacodynamic differences were not noted among the three study groups. Key words A d i n a z o l a m 9 N D M A D
9
Cytochrome P450 9 Ethnicity 9 Benzodiazepine ' Psychotropic 9 Drug metabolism
Introduction
Adinazolam mesylate is a new compound which belongs to the triazolobenzodiazepines, a class of modified benzodiazepines. The main route of elimination of adinazolam is hepatic metabolism to its N-demethyl metabolite (N-demethyladinazolam, N D M A D ) (Fleishaker et al. 1990). This metabolite is cleared primarily through renal excretion and is thought to mediate the psychomotor and sedative effects seen after administration of adinazolam mesylate (Fleishaker et al. 1991b, 1992b, c). It is thought that N D M A D is 25 times more potent at the benzodiazepine receptor than its parent compound (Sethy et al. 1984, 1986). Adinazolam exhibits both antidepressant and anxiolytic properties, although the mechanism(s) of action is not clear. In a previous study eight African-American and eight Caucasian normal volunteers were challenged with adinazolam (20-60mg, PO). During the subsequent 24 h, African-Americans had significantly higher concentrations of N D M A D , but lower concentrations of adinazolam. They also experienced significantly higher levels of sedation and neuromotor impairment, suggesting that such ethnic differences in the pharmacokinetics and pharmacodynamics of adinazolam and its metabolite might be of clinical
266 s i g n i f i c a n c e ( F l e i s h a k e r a n d Phillips 1989; L i n et al. 1993). However, since the s a m p l e size was q u i t e small, the v a l i d i t y o f these f i n d i n g s r e q u i r e d f u r t h e r scrutiny. The pharmacokinetics and pharmacodynamics of a d i n a z o l a m have n o t b e e n p r e v i o u s l y e x a m i n e d i n A s i a n s . However, m a n y studies have i n d i c a t e d t h a t A s i a n s m i g h t be m o r e sensitive to the effects o f vario u s p s y c h o t r o p i c s , b o t h for p h a r m a c o k i n e t i c a n d p h a r m a c o d y n a m i c r e a s o n s ( L i n et al. 1993; L i n a n d P o l a n d 1995). O f p a r t i c u l a r relevance is a s t u d y c o n d u c t e d b y L i n a n d associates (1988a) d e m o n s t r a t i n g t h a t b o t h American-born and foreign-born Asians manifest h i g h e r m a x i m a l a l p r a z o l a m c o n c e n t r a t i o n s (Cma~), larger a r e a u n d e r the c u r v e ( A U C ) values, a n d l o n g e r half-lives t h a n t h e i r m a t c h e d C a u c a s i a n c o u n t e r p a r t s . T h e s e differences r e m a i n e d statistically s i g n i f i c a n t a f t e r i n c l u d i n g b o d y s u r f a c e area as a c o v a r i a t e in the a n a l y sis. Since a l p r a z o l a m a n d a d i n a z o l a m share the s a m e t r i a z o l o b e n z o d i a z e p i n e c h e m i c a l structure, it is likely t h a t s i m i l a r e t h n i c differences m i g h t also exist for the latter c o m p o u n d . I n the f o l l o w i n g we r e p o r t the results o f a s t u d y that was d e s i g n e d to specifically e x a m i n e these issues.
Materials and methods Subjects A total of 39 healthy male volunteers were enrolled in this study. Thirteen were Asian (one Japanese, two Chinese and ten Filipino), 14 were African-American and 12 were Caucasian. The ethnic origin of each subject's parents and maternal and paternal grandparents were required to ensure homogeneity. All volunteers were non-smokers, within 10% of ideal weight for age and height and determined to be healthy by physical examination and standard clinical laboratory tests. Subjects received no known enzyme inducing agents for 30 days, no medications for 7 days and no alcohol for 2 days prior to and during the study (other than different preparations of adinazolam and NDMAD as specified in the study protocol).
Procedures After signing informed consent and fasting from midnight, subjects were randomly assigned to receive one of the following four treatments: (1) 30 mg oral adinazolam mesylate sustained release tablet plus IV placebo (sterile saline), (2) IV infusion of 10 mg adinazolam mesylate plus oral placebo tablet, (3) IV infusion of 30 mg NDMAD plus oral placebo tablet, or (4) placebo infusion of sterile saline plus oral placebo tablet. Oral medications were administered at 8:00 a.m. with 6 oz water and IV infusions were administered concomitantly over 30 min. Lunch was a standard caffeine free meal, given at 12:00 noon. Although subjects were not required to remain sedentary throughout the duration of the study, they refrained from strenuous activities. Venous blood samples (7 ml) were collected into heparinized vacutainers immediately prior to drug administration (8:00 am), and at 15, 30, 32, 35, 40 and 45 rain and at 1.0, 2.0, 3.0, 4.0, 6.0, 16.0 and 24.0 h after drug administration. Blood was spun at 500 g for 20 min at 4~ Aliquots of plasma were frozen at -20~ until analyses were perlbrmed.
As a test for assessing subjects' neuromotor performance, the digit-symbol substitution test (DSST) was administered prior to drug administration and at 0, 1.0, 2.0, 4.0, 6.0 and 24.0 h after dosing. The number of correct responses in 90 s was calculated. Baseline score was determined by the mean result of two tests administered prior to dosing. Sedation was rated simultaneously with each blood draw according to the Nurse-Rated Sedation Scale (Smith and Kroboth 1987).
Assay Plasma samples were assayed for adinazolam and NDMAD concentrations using a validated, sensitive and specific isocratic high performance liquid chromatography (HPLC) method (Fleishaker et al. I989). For adinazolam the inter-assay coefficient of variation at 2.0 ng/ml (lower limit of quantitation) was 6.4%. For NDMAD this figure was 5.8"/,, at 10.0 ng/ml (lower limit of quantitation).
Pharmacokinetic and statistical analysis Pharmacokinetic parameters were determined by model independent analyses (Gibaldi and Perrier 1982). The maximum plasma concentration (Cm~) and the time at which Cma x occurred (Tmax) were determined by inspection of the concentration-time profiles. The terminal elimination rate constant was determined by linear regression of the terminal linear portion of the log concentrationtime profile. The terminal half-life (tl/2) was calculated as tl:2 = 0.693/terminal elimination rate constant. Area under the plasma concentration-time curve (AUC) was determined by trapezoidal rule up to the last time at which a measurable concentration was observed and extrapolated to infinity. Area under the first moment curve (AUMC) was determined in an analogous manner. Mean residence time (MRT) was calculated as MRT = AUMC/ AUC - T/2 where T = infusion duration. Systemic clearance (CL) of adinazolam and NDMAD following IV infusion was calculated as CL = Dose/AUC. Oral total body clearance (CLpo) of adinazolam following oral administration was calculated as CLpo = Dosepo/AUC. Volume of distribution (Vss) following the IV dose of adinazolam and NDMAD was calculated as Vss = CL x MRT. Absolute bioavailability (F) of adinazolam sustained release tablets was calculated as F = AUCpo/AUCiv x Doseiv/ Oosepo. Pharmacodynamic data were either analyzed as percentage change from baseline or as raw values. Differences among ethnic groups within drug were determined using ANOVA for a crossover study at each time point; pair-wise comparisons were conducted using least squares means analysis. Body surface area was calculated as logs = logM x 0.425 + logH x 0.725 + 1.8564 (Du Bois and Du Bois 1916). ANCOVA test was used to control for this parameter. Statistical significance was assumed at P < 0.05. All data analyses were performed using SAS (SAS Institute, SAS User's Guide Version 5, 1985) and SPSS computer programs. The results are presented as mean values and standard deviations.
Results T a b l e 1 s u m m a r i z e s d e m o g r a p h i c s o f t h e subjects. Three subjects withdrew from the study following e n r o l l m e n t , two for p e r s o n a l r e a s o n s a n d o n e for a n o n s e r i o u s m e d i c a l event. P r i o r to a n a l y s i s o f the d a t a b e t w e e n the three s t u d y g r o u p s , each g r o u p was i n d i v i d u a l l y e x a m i n e d to e n s u r e h o m o g e n e i t y w i t h i n groups. T h i s was d o n e p a r t i c u l a r l y b e c a u s e the A s i a n s u b j e c t s
267 Table 1 Sample characteristics: adinazolam study. Pairwise comparison for all three variables revealed difference between Asians and Caucasians and Asians and African-Americans, without significant differences between Caucasians and African-Americans (n)
Age Height (cm) Weight (kg)
Asian (13)
African-American (14)
27.1 _+7.2 168.1 +_6.1 68.4 -+ 7.8
Caucasian (l 2)
31.3 + 5.4 179.5 + 6.3 80.8 _+7.9
ANOVA
36.4 -+ 8.1 178.7 -+ 8.1 75.4 _+ 7.9
F
P
17.8 25.7 17.6
0 0 0
Table 2 Pharmacokinetic parameters of adinazolam and N D M A D Asian
African-American
Caucasian
ANOVA F
ANCOVA P
F
P
Comparison ot" pharmacokinetic parameters after adinazolam (10 rag, IV) Adinazolam AUC(ng.h/ml) Cm,,x (ng/ml) C1 (l/h) tV2 (h) Tmax (min) Vd ...... (1) ND MA D AUC(ng.h/ml) Cma., (ng/ml) tV2 (h)
Tmax (h)
517_+ 177 262 + 63.3 16.7+_5.00 3.29 _+ 1.17 1.60 + 0.80 57.0+ 10.7
385+60.4 192 + 38.4 21.0+3.58 3.17 + 0.90 1.83 + 0.84 73.2_+ ll.1
322_+84.6 186 + 44.3 26.1 _+7.42 2.42 -+ 0.67 1.48 -+ 0,46 69.0_+ 14.9
8.4563 8.6036 8.5820 3.0550 1.3046 5.4738
0.0011 0.0010 0.0010 0.0609 0.2849 0.0088
3.842 2.224 5.763 2,762 0.526 0,143
0.032 0.125 0.007 0,780 0.590 0.867
599 +_ 121 57.7 + 9.8 5.94 +_ 1.31 1.60 + 0.80
504 + 70.7 47.6 + 6.2 5.86 + 1.51 1.83 _+0.84
454 + 105 49.4 + 10.5 5.53 -+ 1.76 1.48 + 0,46
6.3301 4.1870 0.2439 0.7227
0.0047 0.0240 0.7864 0.4930
3.213 0.136 0.365 0,573
0.053 0.873 0,697 0.570
512 + 297 46.1 +_21.8 62.4 + 36.1 7.11 + 3.75 1.81 + 1.21 0.51 +_0.21
2.6382 5.0596 2.9556 0.3000 1.5051 0.3281
0.087 0.012 0.659 0.742 0.237 0,723
0,345 1.545 1.931 0.297 1.424 0.610
0.711 0.229 0.161 0.745 0.256 0.550
1352 94.2 8.46 3.42
1.7532 2.6934 0.6991 0.5676
0.189 0.083 0.503 0,572
0.536 2.100 0.577 0.911
0.590 0.139 0.567 0.418
0.0151 0.0007 0.0093 0.0298 0.4362 0.0001
2.310 4.112 3.380 4.214 2.293 4.528
0.116 0.026 0.047 0.024 0.117 0.019
Comparison of adinazolam pharmacokinetics after adinazolam mesylate (30 mg, PO) Adinazohml AUC(ng.h/ml) Cmax (ng/ml) CI (l/h) tt/2 (h)
Tmax (min) Bioavail ND MA D AUC (ng.h/ml) Cm~x (ng/ml) tV2 (h)
Tmax (h)
810 75.8 37.8 6.44 2.59 0.49
+_ 523 + 32.3 + 16.6 + 3.18 + 1.98 + 0.16
525 52.1 49.2 6.1 3.1 0,45
1641 112 8.30 4.29
+ + + +
1395 -+ 207 107 _+21.3 7.16 + 1.10 3.42 _+ 1.49
542 18.6 4.32 3.00
-+ 155 +_ 15.4 + 16.5 + 2.77 +_2.18 + 0.12
+ 403 +_ 17.1 + 2.45 +- 2.22
Comparison of pharmacokinetic parameters after N D M A D 130 rag, IV) NDMAD AUC(ng.h/ml) Cm,~x (ng/ml) C1 (l/h) tV, (h) Tmax (rain)
Vdarea (1)
2443 777 9.91 3.08
+ 416 + 126 +_ 1.57 + 0.445 0.5 40.0 + 5.4
2195 + 220 618 _+ 167 10.9 + 1.02 3.47 + 0.35 0.5167 50.7 + 6.33
consisted of three different nationalities. Table 2 depicts the pharmacokinetics of adinazolam following all three treatments. Figure 1 shows the pharmacokinetics of adinazolam following 10 mg IV dosing of adinazolam sterile solution. Asians showed significantly higher adinazolam AUC than both Caucasians and AfricanAmericans, and significantly higher Cmax than Caucasians. As depicted in Fig. 3, the pharmacokinetics of N D M A D following administration of 10 mg IV adinazolam were similar for all groups with the exception
2028 + 328 554 + 86.6 11.9 +_ 1.77 3.11 + 0.338 0.5208 49.9 + 5.20
44.7729 92264 5.4047 3,9240 0.8509 13.2833
of higher AUC and Cmaxfor Asians compared to both Caucasians and African-Americans. Figure 2 demonstrates the pharmacokinetics of oral 30 mg adinazolam mesylate SR tablets. Despite an approximately 60% greater adinazolam AUC in Asians than both Caucasians and African-Americans, statistical significance was not reached. This appeared to be primarily due to two Asian subjects whose adinazolam AUCs were unexpectedly high (1921 and 1841 ng.h/ml), causing a greater variance in this group. However, when the
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Fig. 3 Adinazolam concentrations after adinazolam (30 mg PO) in Asian (-A-), African-American ( -@-- ) and Caucasian ( -N-- ) normal volunteers
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Time After Adinazolam Administration (h)
Fig. 1 Adinazolam concentrations after adinazolam (10 mg IV) in Asian (-A-), African-Anaerican ( -@-- ) and Caucasian ( ~ ) normal volunteers
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Fig. 2 N-Desmethyladinazolam ( N D M A D ) concentrations after adinazolana (10 nag IV) in Asian (-A-), African-American ( -@-- ) and Caucasian ( ~ ) normal volunteers
Fig. 4 N-Desmethyladinazolam ( N D M A D ) concentrations after adinazolana (30 nag PO) in Asian (-A-), African-American (-@--) and Caucasian ( @ ) normal volunteers
data were analyzed with the exclusion of the two values, the results still failed to reach statistical significance. Significant differences in N D M A D pharmacokinetics following oral adinazolam mesylate were observed only in Cma• values with Asians significantly higher than Caucasians, but not African-Americans (Fig. 4). Following the administration of NDMAD, 30 rag, significant differences in N D M A D AUC and Cmax were observed between Asians and both AfricanAmericans and Caucasians. African-Americans and Caucasians were not significantly different in these two parameters (Fig. 5). As depicted in Table 2, when body surface area was covaried (ANCOVA), the differences remained significant. Overall, the results of the pharmacodynamic evaluation did not reach statistical significance. However, 4 h after administration of IV adinazolam there was a significant reduction in DSST scores between Caucasians and African-Americans. This significant difference occurred with placebo as well. Otherwise, no significant differences were noted in DSST scores after administration of IV adinazolam among the three ethnic groups. Following administration of oral adinazo-
lam, no significant changes in DSST scores were noted at any point. There were no statistically significant changes in mean NRSS scores following each treatment among the three ethnic groups.
Discussion The pharmacokinetic profiles of adinazolam and N D M A D are similar to those previously reported. Adinazolam is an intermediate acting benzodiazepine which yields an active metabolite, N D M A D , after first pass metabolism. N D M A D is eliminated by active tubular secretion with greater than 50% of the dose of adinazolam recovered in the urine as this metabolite (Fleishaker et al. 1990). The pharmacokinetic results of adinazolam in this study are in keeping with a previous study on alprazolam, another triazolobenzodiazepine, in which Asians were reported to have higher AUC and Cm.~x than Caucasians after both oral and IV dosing (Lin et al. 1988a). The findings in this study with respect to
269 1,000 8OO o
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200
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Time After N D M A D Administration (h)
Fig. 5 N-Desmethyladinazolam (NDMAD) concentrations after NDMAD (30 mg IV) in Asian (-A-) , African-American ( -~-- ) and Caucasian ( --N---) normal volunteers
differences between the metabolism of adinazolam in Caucasians and African-Americans are contradictory to previous reports. Lin et al. reported that AfricanAmericans had significantly lower adinazolam AUC and Cmax and higher clearance than their Caucasian counterparts (Lin et al. 1993). A possible explanation for the different results might be due to heterogeneity within different ethnic groups. Following both IV and PO administration of adinazolam, Asians were substantially slower in the biotransformation of adinazolam and its major metabolite, NDMAD. This resulted in significantly larger AUC and higher C~na• for both adinazolam and NDMAD, as well as significantly lower C1 and longer T1/2 for adinazolam following IV administration of the medicine. After taking into account of the effect of body surface area, most of these differences remained statistically significant at, or close to, the 0.05 level. However, statistical significance largely disappeared in the PO portion of the study. This phenomenon has been reported previously in a study comparing alprazolam kinetics between Asians and Caucasians (Lin et al. 1988a), as well as in a study comparing haloperidol kinetics between the two groups (Lin et al. 1988b). One possible explanation is that there was a larger variance in AUCs among Asians. Another reason may be variability in absorption following PO dosing. However, this explanation is not likely since adinazolam is almost completely absorbed (Fleishaker et al. 1991 a). One explanation for increased AUCs in Asians is that Asians might metabolize adinazolam less extensively, leading to higher AUCs of adinazolam. This may be secondary to slower activity of cytochrome P450 3A3/4 which is responsible for phase I metabolism of adinazolam (Greenblatt et al. 1996). The fact that the differences remained significant after controlling for body surface area indicates the possibility that the mean body size in the three study groups accounted for the differences in AUC. Likewise, one can speculate that AfricanAmericans have lower adinazolam AUC possibly because the activity of cytochrome P450 3A3/4 may
be greater in this ethnic group, although this has not been reported. The actual mechanisms underlying differential action of cytochrome p450 3A3/4 are unclear at this time and much of the discussion throughout the literature is theoretical. Unlike cytochrome p450 2D6, polymorphisms for cytochrome p450 3A3/4 have not been well established. Several studies point out kinetic differences in the metabolism of certain cytochrome p450 3A3/4 substrates among ethnic groups. One study compared the kinetics of nifedipine among South Asians and British Caucasians (Chowdhury et al. 1993). Slower activity of cytochrome p450 3A3/4 was observed in South Asians. The present study as well as the prior alprazolam study (Lin et al. 1993) reveal similar results. Despite substantial kinetic differences, pharmacodynamic differences did not reach statistical significance. The digit symbol substitution test may not be a sufficiently sensitive measure of psychomotor performance. More sensitive measures may be necessary to assess pharmacodynamic effects of adinazolam. In the study of Fleishaker et al. (1992a), AfricanAmericans were found to have higher sedation and greater reduction in psychomotor performance scores than Caucasians. In light of the fact that N D M A D has a much higher affinity for the benzodiazepine receptor than the parent compound, and appears to mediate the benzodiazepine effect, it is conceivable that AfricanAmericans have a higher metabolic capacity for adinazolam (Lin and Poland 1995). Based on the results of our study, and a review of previous studies on benzodiazepines (Lin et al. 1988a, 1986, 1993; Lin and Poland 1995), it seems likely that Asian patients will require smaller doses of adinazolam than Caucasian patients to achieve similar levels of adinazolam and NDMAD. African-American patients tend to exhibit more of the benzodiazepine effects of adinazolam, quite possibly due to a more extensive metabolism of adinazolam to its active metabolite.
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270 Fleishaker JC, Friedman H, Pollock SR (1991a) Extent and variability in first pass elimination of adinazo[am mesylate in healthy male volunteers. Pharm Res 8:162-167 Fleishaker JC, Smith TC, Friedman H, Phillips JP (1991b) Ndesmethyladinazolam pharmacokinetics and behavioral effects following administration of 10 to 50 mg oral doses in healthy volunteers. Psychopharmacology 105 : 18I- 185 Fleishaker JC, Hulst LK, Ekernas S-A, Grahnen A (1992a) Pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam after oral and intravenous dosing in healthy young and elderly volunteers. J Clin Psychopharmacol 12:403-414 Fleishaker JC, Hulst LK, Smith TC, Friedman H (1992b) Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate following single intravenous infusions of each compound in healthy volunteers. Eur J Clin Pharmacol 42: 287-294 Fleishaker JC, Smith TC, Friedman H, Hulst LK (1992c) Separation of the pharmacokinetic/pharmacodynamic properties of oral and IV adinazolam mesylate and N-desmethyladi~ nazolam mesylate in healthy volunteers. Drug Invest 4: 155-165 Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Marcell Dekker, New York Greenblatt D J, Ehrenberg BL, Harmatz JS, Fleishaker JC, Corbett K, Hurrel L, Shader RI (1996) Comparative pharmacodynamics of intravenous alprazolam, adinazolam and desmethyladinazolam. Clin Pharmacol Ther 59:178 (abstract)
Lin KM, Poland RE (1995) Ethnicity, culture and psychopharmacology. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven Press, New York, pp 1907 1917 Lin KM, Poland RE, Lesser IM (1986) Ethnicity and psychopharmacology. Culture. Med Psychiatry 10:151-165 Lin KM, Lau JK, Smith RB, Phillips JP, Antal EJ, Poland RE (1988a) Comparison of alprazolam plasma levels in normal Asian and Caucasian volunteers. Psychopharmacology 96:365 369 Lin KM, Poland RE, Lau JK, Rupin RT (1988b) Haloperidol and prolactin concentrations in Asians and Caucasians. J Clin Psychopharmacol 8:195-201 Lin KM, Poland RE, Nakasaki G (1993) Psychopharmacology and psychobiology of ethnicity. American Psychiatric Press, Washington DC, pp 91-105 SAS Institute (1985) SAS user's guide, Version 5. SAS Institute, Cary N.C. Sethy VH, Collins RJ, Daniels EG (1984) Determination of biological activity of adinazolam and its metabolite. J Pharm Pharmacol 36:546-548 Sethy VH, Francis JW. Day JS (1986) The effect of proadifen on the metabolism of adinazolam. J Pharm Pharmacol 38:631-632 Smith RB, Kroboth PD (1987) Influence of dosing regimen of alprazolam and metabolite serum concentrations and tolerance to sedative and psychomotor effects. Psychopharmacology 93: 105-112
