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Kinetics of Diazepam, Midazolam, and Lorazepam in Cigarette Smokers
Kinetics of Diazepam, Midazolam, and Lorazepam in Cigarette Smokers· Hermann R. Ochs, M.D.; David]. Greenblatt, M.D.; and
Martin Knuchel, M.D.
Ten otherwise healthy cigarette smokers (mean, 31 cigarettes per day), and ten nonsmoking control volunteers matched for age, weight, and sex received single intravenous doses of diazepam (5 to 10 mg), midazolam (5 mg), and lorazepam (2 mg) on three separate occasions. Kinetics of each benzodiazepine were determined from multiple serum concentrations measured after each dose. In non-
smoking vs smoking subjects, there was no signi6cant difference in mean clearance of diazepam (0.44 vs 0.47 ml/min/kg), midazolam (9.6 vs 7.1 ml/min/kg), or lorazepam (0.96 vs 1.08 ml/minlkg). Thus, differences in pharmacokinetics are unlikely to account for altered sensitivity to benzodiazepines that may occur in cigarette smokers.
The hydrocarbons contained in cigarette smoke are known to be inducers of hepatic microsomal drug metabolizing enzymes. Clinical studies have shown enhanced clearance of a number of drugs in cigarette smokers as compared to nonsmoking control subjects.!" Many individuals who take benzodiazepines for the treatment of anxiety or sleep disorders also are cigarette smokers, and some studies have suggested reduced sensitivity to diazepam and chlordiazepoxide in patients who smoke cigarettes. 6 The present study was designed to evaluate whether alterations in benzodiazepine pharmacokinetics among cigarette smokers might explain apparently reduced clinical sensitivity, since increased clearance ofbenzodiazepines would lead to reduced steady-state concentrations during multiple dosage. We evaluated the kinetics of intravenous (IV) diazepam and midazolam, two benzodiazepines metabolized principally by microsomal oxidation," as well as the kinetics of IV lorazepam, a benzodiazepine biotransformed by glucuronide conjugation. 8
Control and cigarette smoking subjects did not differ significantly in age, weight, or gender composition. All were healthy, active, ambulatory adults with no history of medical disease and were taking no other medications. Female subjects were not taking oral contraceptives.
METHODS
Subjects Cigarette smoking subjects were ten healthy volunteers, six men and four women, aged 22 to 37 years (mean, 27 years). Their mean weight was 68 kg. They smoked an average of 31 cigarettes per day (range, 25 to 45) and had been cigarette smokers for at least one year prior to the study. Control subjects were ten healthy nonsmoking volunteers, six men and four women, aged 22 to 31 years (mean, 26 years). Their mean weight was 66 kg. Cigarette smoking or nonsmoking habits were accepted as valid as stated by the volunteers; we did not attempt other means of validation. *From the Medizinische Universitatsklinik, University of Bonn, Federal Republic of Germany; and the Division of Clinical Pharmacology, Tufts-New England Medical Center, Boston. Supported in part by grant Oc 10/6-4 from Deutsche Forschungsgemeinschaft, and by grant MH-34223 from the United States Public Health Service. Manuscript received April 23; revision accepted July 17. Reprint requests: Dr. Greenblatt, Box 1007, Division of Clinical Phannacology, Tufts-New England Medical Center, Boston 02111
Diazepam Study Control subjects and cigarette smokers each received 5- to lO-mg of diazepam by rapid IV infusion. Venous blood samples were drawn into additive-free tubes prior to and at multiple points in time during the first 24 hours after dosage, then every 24 hours up to seven days after the diazepam dosage. Blood samples were centrifuged, and the serum separated and frozen until the time of assay. Concentrations of diazepam and its major metabolite, desmethyldiazepam, in each serum sample were determined by electron capture gas liquid chromatography. 9 The extent of diazepam binding to plasma protein in a single sample from each subject was determined by equilibrium dialysis. 10 M idazolam Study
The ten control subjects and eight of the ten cigarette smokers received a single 5-mg dose of midazolam IV. Venous blood samples were drawn into additive-free tubes at multiple points in time during the next 24 hours. The samples were centrifuged, and the serum separated and frozen until the time of assay. Concentrations of midazolam in all samples were determined by electron capture gas liquid chromatography.l':" The extent of midazolam binding to plasma protein was determined by equilibrium dialysis. 10
Lorazepam Study Control subjects and cigarette smokers received a single 2-mg dose of lorazepam IV. Multiple venous blood samples were drawn during the first 24 hours after dosage. then every 12 to 24 hours until 72 postdosage. Venous blood samples were centrifuged. and the serum separated and frozen until the time of assay. Concentrations of lorazepam in all samples were determined by electron capture gas liquid chromatography. 13 The extent oflorazepam binding to plasma protein for each subject was determined by equilibrium dialysis. 10
Pharmacokinetic Analysis Serum concentrations of diazepam. midazolam, or lorazepam were analyzed by iterative nonlinear least-squares regression techniques." Data points were fitted to a linear sum of two or three exponential terms. Coefficients and exponents from the fitted function were used to determine volume of distribution using the CHEST I 87 I 2 I FEBRUARY, 1985
223
Tahle I-Kinetics of Diazepam, Midazolom, and Lorazepam in Cigarette Smokers and Nonsmokers Mean (± SE) Values A~ent
Diazepam Volume of distrihution, IJk~ Elimination half-life. hr Total AVe, ILlt"ml x hr Total clearance, ml/rnin/kg Free fraction, % unbound Midazolam Volume of distribution, rJk~ Elimination half-life, hr Total AVe, ILlt"ml x hr Total clearance, ml/min!kJ1; Free fraction, % unbound Lorazepam Volume of distribution. 11kJ1; Elimination half-life, hr Total AVe, lL!1:Iml x hr Total clearance, ml/min/kg Free fraction, % unhound
Nonsmokers
Smokers
1.22( ± .10) 3.1.5(± 2.9) 4.73(± .58) O.44(±.OS) 1.42(± .05)
1.20(±.1O) 31.3(±3.5) 3.83(±.34) 0.47(±.04) 1.33(± .04)
0.17 (NS) 0.49 (NS) 1.32 (NS) 0.42 (NS) 1.38 (NS)
1.60(± .17) 2.0(±.2) O.l.'j(± .01) 9.6( ± 1.2) 3.41 (± .09)
1.31( ± .25) 2.2(±.28) 0.17(±.03) 7.1(±.9) 3.19(± .08)
0.99 0.54 0.73 1.57 1.72
(NS) (NS) (NS) (NS) (NS)
1.30( ± .07) 16.4( ± 1.2) 0.58(±.07) 0.96(±.09) 8.0(±.3)
1.22(± .03) 13.3(±O.7) 0.47(±.02) 1.08(±.OS) 7.9(±.1)
1.10 2.32 1.61 1.13 0.50
(NS) (p<.05) (NS) (NS) (NS)
diazepam was lower in smokers than in control subjects (3.51 vs 4.54 f.Lg/ml X hr; t = 2.27, p<.05), but the difference was not significant when AVC was normalized for body weight (246 vs 298 f.Lg/ml x hr x kg, t = 1.35; NS). For midazolam, there was no difference between the two groups in any of the kinetic variables. In the case of lorazepam, volume of distribution did not differ significantly between groups. Elimination half-life was slightly shorter in smokers as compared to control subjects (p<.05), but the slight increase in total lorazepam clearance (1.08 vs 0.93 mllminlkg) did not reach significance. Lorazepam free fraction was no different between the two groups.
area method, elimination half-life, total area under the curve (AVe), and total clearance. Desmethyldiazepam, the major metaholite of diazepam, appeared in the serum of all patients after IV injection of diazepam. Although the duration of sampling was not sufficient for formal pharmacokinetic analysis, AVe for desmethyldiazepam from time zero to seven days after diazepam dosage was determined by the trapezoidal method. Differences between control and cigarette smoking subjects were evaluated by Student's independent t test. RESUl;rs
Table 1 summarizes pharmacokinetic findings in nonsmoking control suhjects and cigarette smokers (Fig 1). For diazepam, differences hetween groups in volume of distrihution, elimination half-life, total AVC, total clearance, and free fraction did not approach significance. Mean AVC for desmethyl-
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Diazepam Desmethyldiazepom
LORAZEPAM 2mg iv.
• 10
• 10
. . . . _-<)0.
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Cigarette smoking is known to induce the activity of
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DISCUSSION
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300 100
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4
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48
72
FIGURE 1. Serum concentrations in a nonsmoking volunteer following intravenous administration of diazepam, midazolam, and lorazepam,
224
Diazepam. Midazolam, Lorazepam in CigaretteSmokers(OChs. Gl8flnblatt. KnOChel)
certain microsomal enzymes. A number of studies have demonstrated increased clearance of drugs in cigarette smokers.!" and some clinical studies have suggested decreased clinical efficacy and/or decreased rates of clinical toxicity in cigarette smoking populations as compared to matched control subjects. 6.15-17 Such clinical findings have been reported in the case of the benzodiazepine derivatives chlordiazepoxide and diazepam." However, the apparently reduced clinical sensitivity to benzodiazepines among cigarette smokers has not yet been directly related to alterations in benzodiazepine pharmacokinetics. The present study evaluated the kinetics of three benzodiazepines in moderate to heavy cigarette smokers as compared to age-, sex-, and weight-matched control subjects. Diazepam is metabolized principally by microsomal oxidation, having a total clearance considerably less than hepatic blood flow. 7 As such, its clearance should be influenced primarily by hepatic microsomal drug metabolizing activity." Diazepam clearance is enhanced by rifampin," and inhibited by isoniazid, 19 oral contraceptive steroids." cimetidine," and propranolol. 22 However, there were no significant differences between control and cigarette smoking subjects in any of the kinetic variables for diazepam, Midazolam likewise is metabolized principally by microsomal oxidation, but its hepatic clearance is considerably higher, being approximately 50 percent of hepatic blood flow. 12.2.1 Midazolam clearance after IV dosage will depend on microsomal oxidizing activity, as well as hepatic blood How IH Again, however, there was no difference between control and smoking groups in the kinetics of a single IV dose of midazolam. In the case of lorazepam, metabolized principally by the usually resistant pathway of glucuronide conjugation, H there was a small and statistically insignificant trend toward increased clearance of lorazepam in smokers as compared to control subjects. In previous studies from our laboratory that were not specifically designed for assessment of smoking effects on drug metabolism, multiple regression analysis has demonstrated a small contribution of cigarette smoking to the clearance of a number ofbenzodiazepines, in the direction of increased clearance attributable to smoking.":" In one study, cigarette smoking was associated with significantly increased clearance of a single oral dose of oxazepam. 26 In the present study, specifically designed to evaluate the effect of smoking as such, minimal if any influence of smoking on benzodiazepine kinetics could be observed. The findings suggest that pharmacokinetic changes do not explain any alterations in clinical sensitivity to benzodiazepines that might occur among cigarette smokers. ACKNOWLEDGEMENT: We are grateful lor the assistance of Rita Matlis, Ann Locniskar, and Marcia K. Divoll.
REFEHENCES lOchs HR, Verburg-Ochs B. Eillnu~ von Alter, Gewicht, Geschlecht und Hauchgewohuheiten auf die Medikamentendosierung. Internist 1983; 24:167-Ml 2 Dawson GW, Vestal RE. Smoking and drug metabolism. Pharmacol Ther 1982; 15:207-21 3 J usko w], Role of tobacco smoking in pharmacokinetics. J Pharmaeokinet Biopharm 1978; 6:7-39 4 Jusko WJ. Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev 1979; 9:221-36 5 Eichelbaum ~I, Ochs HN, Roberts G, Somogyi A. Pharmacokinetics and metabolism of antipyrine (Phenazone] after intravenous and oral admiuistration. Arzneunitteltorsch 1982; 32:575-M 6 Boston Collaborative Drug Surveillance Program. Clinical depression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. N Engl J Med 1973; 288:277-MO 7 Greenblatt OJ, Divoll ~1, Abernethy DR, Ochs HR, Shader RI. Benzodiazepine kinetics: implications for therapeutics and pharmacogeriatrics. Drug Metab Rev 1983; 14:251-92 8 Greenblatt DJ. Clinical phannacokiuetics of oxazepam and lorazepam. Clin Phanuacokinet 1981; 6:88-10.5 9 Greenblatt OJ, Ochs HR, Lloyd BL. Entry of diazepam and its major metabolite into cerebrospinal fluid. Psychopharmacology (Berlin) 1980; 70:89-93 10 Moschitto LJ, Greenblatt I) J. Concentration-independent plasma protein binding of benzodiazepines. j Pharm Phannacol 1983; 35:179-80 11 Arendt RM, Greenblatt OJ, Garland WA. Quantitation by gas chromatography of the 1- and 4-hydroxy metabolites of midazolam in human plasma. Pharmacology 1984; 29:158-64 12 Greenblatt OJ, Locniskar A, Ochs HH, Lauven P~I. Automated gas chromatography for studies of midazolam pharmacokinetics, Anesthesiology 1981; 55: 176-9 13 Greenblatt DJ, Franke K, Shader RI. Analysis of lorazepam and its glucuronide rnetabolite by electron-capture gas-liquid chromatography: use in phannacokinetic studies of lorazepam. J Chromatogr 1978; 146:311-20 14 Ochs HR, Bodern G, Bales C, Greenblatt D], Smith T\V. Increased clearance of digoxin in rabbits during repeated adrninistration. J Pharmacol Exp Ther 1978; 205:516-24 15 Miller RR. Effects of smoking on drug action. Clin Pharmacol Ther 1977; 22:749-56 16 Pfeifer Hj, Greenblatt DJ. Clinical toxicity of theophylline in relation to cigarette smoking: a report from the Boston Collaborative Drug Surveillance Program. Chest 1978; 73:455-9 17 Gugler R, Jusch E. Cimetidin und neuere H 2-Rezeptorenblocker in der Therapie gastrointestinaler Erkrankungen. Med Welt 1982; 31:1083-7 18 Wilkinson GR, Shand DC. A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975; 18:377-90 19 Ochs HR, Greenblatt OJ, Roberts (;-M, Dengler HJ. Diazepam interaction with antituberculosis drugs. Clin Pharmacol Ther 1981; 29:671-9 20 Abernethy DR, Greenblatt OJ, Divoll M, Arendt R, Ochs HR, Shader RI. Impairment of diazepam metabolism by low-dose estrogen oral contraceptive steroids. N Engl J Med 1982; 306:791-2 21 Abernethy DR, Greenblatt OJ, Divoll ~t, Ameer B, Shader HI. Differential effect of cimetidine on drug oxidation (antipyrine and diazepam) versus conjugation (acetaminophen and lorazepam): prevention of acetaminophen toxicity by cimetidine, J Pharmacol Exp Ther 1983; 224:508-13 22 Ochs HR, Greenblatt DJ, Abernethy DR. Propranolol impairs diazepam oxidation but not lorazepam conjugation. Clin Pharmacol Ther 1984; 35:263 CHEST I 87 I 2 I FEBRUARY, 1985
225
23 Greenblatt D}, Abernethy DR, Locniskar A, Harmatz }S, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 1984; 61:27-35 24 Greenblatt OJ, Allen MO, Locniskar A, Harmatz JS, Shader RI. Lorazepam kinetics in the elderly. Clin Pharmacol Ther 1979; 26:103-13
221
25 Greenblatt D}, Allen MD, Harmatz }5, Shader RI. Diazepam disposition determinants. Clin Pharmacol TIter 1980; 27:301-12 26 Ochs HR, Greenblatt D}, Otten H. Disposition of oxazepam in relation to age, sex, and cigarette smoking. Klin Wochenschr 1981; 59:899-903
Dlaz.pam, Mldazolam, Loraz.pam In Clga,.n. Smok.rI (OChl, Ore.nblatt, KnOCh")
Martin Knuchel, M.D.
Ten otherwise healthy cigarette smokers (mean, 31 cigarettes per day), and ten nonsmoking control volunteers matched for age, weight, and sex received single intravenous doses of diazepam (5 to 10 mg), midazolam (5 mg), and lorazepam (2 mg) on three separate occasions. Kinetics of each benzodiazepine were determined from multiple serum concentrations measured after each dose. In non-
smoking vs smoking subjects, there was no signi6cant difference in mean clearance of diazepam (0.44 vs 0.47 ml/min/kg), midazolam (9.6 vs 7.1 ml/min/kg), or lorazepam (0.96 vs 1.08 ml/minlkg). Thus, differences in pharmacokinetics are unlikely to account for altered sensitivity to benzodiazepines that may occur in cigarette smokers.
The hydrocarbons contained in cigarette smoke are known to be inducers of hepatic microsomal drug metabolizing enzymes. Clinical studies have shown enhanced clearance of a number of drugs in cigarette smokers as compared to nonsmoking control subjects.!" Many individuals who take benzodiazepines for the treatment of anxiety or sleep disorders also are cigarette smokers, and some studies have suggested reduced sensitivity to diazepam and chlordiazepoxide in patients who smoke cigarettes. 6 The present study was designed to evaluate whether alterations in benzodiazepine pharmacokinetics among cigarette smokers might explain apparently reduced clinical sensitivity, since increased clearance ofbenzodiazepines would lead to reduced steady-state concentrations during multiple dosage. We evaluated the kinetics of intravenous (IV) diazepam and midazolam, two benzodiazepines metabolized principally by microsomal oxidation," as well as the kinetics of IV lorazepam, a benzodiazepine biotransformed by glucuronide conjugation. 8
Control and cigarette smoking subjects did not differ significantly in age, weight, or gender composition. All were healthy, active, ambulatory adults with no history of medical disease and were taking no other medications. Female subjects were not taking oral contraceptives.
METHODS
Subjects Cigarette smoking subjects were ten healthy volunteers, six men and four women, aged 22 to 37 years (mean, 27 years). Their mean weight was 68 kg. They smoked an average of 31 cigarettes per day (range, 25 to 45) and had been cigarette smokers for at least one year prior to the study. Control subjects were ten healthy nonsmoking volunteers, six men and four women, aged 22 to 31 years (mean, 26 years). Their mean weight was 66 kg. Cigarette smoking or nonsmoking habits were accepted as valid as stated by the volunteers; we did not attempt other means of validation. *From the Medizinische Universitatsklinik, University of Bonn, Federal Republic of Germany; and the Division of Clinical Pharmacology, Tufts-New England Medical Center, Boston. Supported in part by grant Oc 10/6-4 from Deutsche Forschungsgemeinschaft, and by grant MH-34223 from the United States Public Health Service. Manuscript received April 23; revision accepted July 17. Reprint requests: Dr. Greenblatt, Box 1007, Division of Clinical Phannacology, Tufts-New England Medical Center, Boston 02111
Diazepam Study Control subjects and cigarette smokers each received 5- to lO-mg of diazepam by rapid IV infusion. Venous blood samples were drawn into additive-free tubes prior to and at multiple points in time during the first 24 hours after dosage, then every 24 hours up to seven days after the diazepam dosage. Blood samples were centrifuged, and the serum separated and frozen until the time of assay. Concentrations of diazepam and its major metabolite, desmethyldiazepam, in each serum sample were determined by electron capture gas liquid chromatography. 9 The extent of diazepam binding to plasma protein in a single sample from each subject was determined by equilibrium dialysis. 10 M idazolam Study
The ten control subjects and eight of the ten cigarette smokers received a single 5-mg dose of midazolam IV. Venous blood samples were drawn into additive-free tubes at multiple points in time during the next 24 hours. The samples were centrifuged, and the serum separated and frozen until the time of assay. Concentrations of midazolam in all samples were determined by electron capture gas liquid chromatography.l':" The extent of midazolam binding to plasma protein was determined by equilibrium dialysis. 10
Lorazepam Study Control subjects and cigarette smokers received a single 2-mg dose of lorazepam IV. Multiple venous blood samples were drawn during the first 24 hours after dosage. then every 12 to 24 hours until 72 postdosage. Venous blood samples were centrifuged. and the serum separated and frozen until the time of assay. Concentrations of lorazepam in all samples were determined by electron capture gas liquid chromatography. 13 The extent oflorazepam binding to plasma protein for each subject was determined by equilibrium dialysis. 10
Pharmacokinetic Analysis Serum concentrations of diazepam. midazolam, or lorazepam were analyzed by iterative nonlinear least-squares regression techniques." Data points were fitted to a linear sum of two or three exponential terms. Coefficients and exponents from the fitted function were used to determine volume of distribution using the CHEST I 87 I 2 I FEBRUARY, 1985
223
Tahle I-Kinetics of Diazepam, Midazolom, and Lorazepam in Cigarette Smokers and Nonsmokers Mean (± SE) Values A~ent
Diazepam Volume of distrihution, IJk~ Elimination half-life. hr Total AVe, ILlt"ml x hr Total clearance, ml/rnin/kg Free fraction, % unbound Midazolam Volume of distribution, rJk~ Elimination half-life, hr Total AVe, ILlt"ml x hr Total clearance, ml/min!kJ1; Free fraction, % unbound Lorazepam Volume of distribution. 11kJ1; Elimination half-life, hr Total AVe, lL!1:Iml x hr Total clearance, ml/min/kg Free fraction, % unhound
Nonsmokers
Smokers
1.22( ± .10) 3.1.5(± 2.9) 4.73(± .58) O.44(±.OS) 1.42(± .05)
1.20(±.1O) 31.3(±3.5) 3.83(±.34) 0.47(±.04) 1.33(± .04)
0.17 (NS) 0.49 (NS) 1.32 (NS) 0.42 (NS) 1.38 (NS)
1.60(± .17) 2.0(±.2) O.l.'j(± .01) 9.6( ± 1.2) 3.41 (± .09)
1.31( ± .25) 2.2(±.28) 0.17(±.03) 7.1(±.9) 3.19(± .08)
0.99 0.54 0.73 1.57 1.72
(NS) (NS) (NS) (NS) (NS)
1.30( ± .07) 16.4( ± 1.2) 0.58(±.07) 0.96(±.09) 8.0(±.3)
1.22(± .03) 13.3(±O.7) 0.47(±.02) 1.08(±.OS) 7.9(±.1)
1.10 2.32 1.61 1.13 0.50
(NS) (p<.05) (NS) (NS) (NS)
diazepam was lower in smokers than in control subjects (3.51 vs 4.54 f.Lg/ml X hr; t = 2.27, p<.05), but the difference was not significant when AVC was normalized for body weight (246 vs 298 f.Lg/ml x hr x kg, t = 1.35; NS). For midazolam, there was no difference between the two groups in any of the kinetic variables. In the case of lorazepam, volume of distribution did not differ significantly between groups. Elimination half-life was slightly shorter in smokers as compared to control subjects (p<.05), but the slight increase in total lorazepam clearance (1.08 vs 0.93 mllminlkg) did not reach significance. Lorazepam free fraction was no different between the two groups.
area method, elimination half-life, total area under the curve (AVe), and total clearance. Desmethyldiazepam, the major metaholite of diazepam, appeared in the serum of all patients after IV injection of diazepam. Although the duration of sampling was not sufficient for formal pharmacokinetic analysis, AVe for desmethyldiazepam from time zero to seven days after diazepam dosage was determined by the trapezoidal method. Differences between control and cigarette smoking subjects were evaluated by Student's independent t test. RESUl;rs
Table 1 summarizes pharmacokinetic findings in nonsmoking control suhjects and cigarette smokers (Fig 1). For diazepam, differences hetween groups in volume of distrihution, elimination half-life, total AVC, total clearance, and free fraction did not approach significance. Mean AVC for desmethyl-
......
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70
Z
40
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~ Z
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~
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40
10
Diazepam Desmethyldiazepom
LORAZEPAM 2mg iv.
• 10
• 10
. . . . _-<)0.
10
LJ
Cigarette smoking is known to induce the activity of
10
•
UJ U
DISCUSSION
70
DIAZEPAM 5mgiv
300 100
Student's t test
$
3
"'0
•
o
o
i
2
,
i i i
3 456 DAYS AFTER DOSE
4
•
"
7
4
• o j
I
2
4 6
0 12 HOURS AFTER DOSE
24
48
72
FIGURE 1. Serum concentrations in a nonsmoking volunteer following intravenous administration of diazepam, midazolam, and lorazepam,
224
Diazepam. Midazolam, Lorazepam in CigaretteSmokers(OChs. Gl8flnblatt. KnOChel)
certain microsomal enzymes. A number of studies have demonstrated increased clearance of drugs in cigarette smokers.!" and some clinical studies have suggested decreased clinical efficacy and/or decreased rates of clinical toxicity in cigarette smoking populations as compared to matched control subjects. 6.15-17 Such clinical findings have been reported in the case of the benzodiazepine derivatives chlordiazepoxide and diazepam." However, the apparently reduced clinical sensitivity to benzodiazepines among cigarette smokers has not yet been directly related to alterations in benzodiazepine pharmacokinetics. The present study evaluated the kinetics of three benzodiazepines in moderate to heavy cigarette smokers as compared to age-, sex-, and weight-matched control subjects. Diazepam is metabolized principally by microsomal oxidation, having a total clearance considerably less than hepatic blood flow. 7 As such, its clearance should be influenced primarily by hepatic microsomal drug metabolizing activity." Diazepam clearance is enhanced by rifampin," and inhibited by isoniazid, 19 oral contraceptive steroids." cimetidine," and propranolol. 22 However, there were no significant differences between control and cigarette smoking subjects in any of the kinetic variables for diazepam, Midazolam likewise is metabolized principally by microsomal oxidation, but its hepatic clearance is considerably higher, being approximately 50 percent of hepatic blood flow. 12.2.1 Midazolam clearance after IV dosage will depend on microsomal oxidizing activity, as well as hepatic blood How IH Again, however, there was no difference between control and smoking groups in the kinetics of a single IV dose of midazolam. In the case of lorazepam, metabolized principally by the usually resistant pathway of glucuronide conjugation, H there was a small and statistically insignificant trend toward increased clearance of lorazepam in smokers as compared to control subjects. In previous studies from our laboratory that were not specifically designed for assessment of smoking effects on drug metabolism, multiple regression analysis has demonstrated a small contribution of cigarette smoking to the clearance of a number ofbenzodiazepines, in the direction of increased clearance attributable to smoking.":" In one study, cigarette smoking was associated with significantly increased clearance of a single oral dose of oxazepam. 26 In the present study, specifically designed to evaluate the effect of smoking as such, minimal if any influence of smoking on benzodiazepine kinetics could be observed. The findings suggest that pharmacokinetic changes do not explain any alterations in clinical sensitivity to benzodiazepines that might occur among cigarette smokers. ACKNOWLEDGEMENT: We are grateful lor the assistance of Rita Matlis, Ann Locniskar, and Marcia K. Divoll.
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23 Greenblatt D}, Abernethy DR, Locniskar A, Harmatz }S, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 1984; 61:27-35 24 Greenblatt OJ, Allen MO, Locniskar A, Harmatz JS, Shader RI. Lorazepam kinetics in the elderly. Clin Pharmacol Ther 1979; 26:103-13
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Dlaz.pam, Mldazolam, Loraz.pam In Clga,.n. Smok.rI (OChl, Ore.nblatt, KnOCh")