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The pharmacokinetics and bioavailability of desmethyldiazepam (DMDZ), formed from its precursor clorazepate (CZP) dipotassium, were assessed in a series of 17 healthy volunteers aged 21--66 years. After a single 20-mg intravenous dose of CZP, mean kinetic variables for DMDZ were: volume of distribution, 1.24 l/kg; elimination half-life, 65 h; total clearance, 0.24 ml/min/kg. Among males, DMDZ half-life tended to be prolonged and clearance reduced with age, but this was not true for females. After oral administration of 20 mg CZP, appearance of DMDZ in the circulation was rapid; the mean peak plasma level was 356 ng/ml, reached an average of 0.9 h after dosage. Based on comparison with IV dosage, systemic availability of DMDZ was complete (100% absorption). Ten of the subjects also received a single 20-mg intramuscular dose of CZP. Mean peak DMDZ levels were 290 ng/ml, reaching an average of 2.7 h after dosage. Systemic availability of DMDZ was complete. Elimination half-life of DMDZ for a given individual was highly replicable from trial to trial regardless of the route of CZP administration.

Healthy volunteers received a single dose of triazolam (0.5 mg) or oxazepam (30 mg) on two occasions, once in the control state and again during coadministration of isoniazid (INH) base, 180 mg day. INH coadministration prolonged triazolam half-life (3.3 vs 2.5 h, P less than 0.05) and increased total area under the curve (38.6 vs 26.5 ng ml-1 h, P less than 0.01) consistent with a reduction of apparent oral clearance (3.9 vs 6.8 ml min-1 kg-1, 0.05 less than P less than 0.1). INH coadministration had no influence on the kinetics of oxazepam. INH impairs hepatic microsomal oxidation of triazolam, leading to reduced first-pass hepatic extraction as well as prolonged half-life. However INH had no influence on oxazepam conjugation.

Nitrazepam pharmacokinetics were studied in 14 obese (mean +/- s.e. mean body weight 107 +/- 9 kg; percent ideal body weight [IBW] 166 +/- 12%) and 14 normal body weight (63 +/- 3 kg; percent IBW 98 +/- 2%) subjects. After an overnight fast, each subject ingested 10 mg nitrazepam orally. Nitrazepam concentrations were determined in plasma samples obtained over the following 72 h. Comparison of peak nitrazepam plasma concentration (94.2 +/- 10.3-obese vs 119 +/- 14.6 ng ml-1; NS) and time required after drug administration to reach peak concentration (1.52 +/- 0.24-obese vs 1.59 +/- 0.36 h; NS) indicated no differences between obese and control subjects. Elimination half-life was markedly increased in obese subjects (33.5 +/- 2.2 vs 23.9 +/- 1.2 h; P less than 0.001) due to increased apparent volume of distribution (Vd) (290 +/- 45 vs 137 +/- 12 l; P less than 0.005). Oral clearance was also increased in the obese subjects (101 +/- 12.4 vs 66.8 +/- 12.4 ml min-1; P less than 0.02). Extent of nitrazepam binding to plasma proteins was slightly decreased in obese subjects (% unbound--19.7 +/- 0.4-obese vs 17.9 +/- 0.3%; P less than 0.005). Correction of both Vd (2.62 +/- 0.17-obese vs 2.22 +/- 0.19 l kg-1; NS) and clearance (0.93 +/- 0.06-obese +/- 1.07 +/- 0.07 ml min-1 kg-1; NS) for total body weight (TBW) suggested that increases in obese subjects of both of these parameters were a function of body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of a single 30-mg oral dose of oxazepam was evaluated in seven patients with chronic renal failure on maintenance hemodialysis and in seven healthy controls matched for age and sex. Based on total (free plus bound) serum oxazepam concentrations, elimination half-life was prolonged in renal patients compared to controls (22 vs 8 h, p less than 0.001) and volume of distribution increased (3.0 vs 1.4 1/kg, p less than 0.02). However, total clearance was similar between groups (1.8 vs 1.9 ml/min per kilogram). These findings were confounded by the increased oxazepam free fraction in serum of renal failure patients (10.3%) as compared to healthy controls (4.3%). Correction for differences in binding indicates similar distribution of unbound oxazepam between groups, but reduced clearance of pharmacologically active unbound oxazepam in renal patients (18 vs 45 ml/min per kilogram). Oxazepam dosage, therefore, may require downward adjustment for renal failure patients on hemodialysis.

Bei 6 gesunden Versuchspersonen wurde die biologische Verfugbarkeit von Digoxin und von zwei Digoxin-Kombinationspraparaten (Theophyllin- Theobromin-Digoxin, Carbochromen-Digoxin) nach einer einmaligen oralen Dosis, die 1 mg Digoxin entsprach, untersucht. Uber 18 Std wurden die Digoxin-Serumspiegel radioimmunologisch bestimmt, die varianzanalytisch bei den drei gepruften Medikamenten keine signifikanten Unterschiede aufwiesen. Von diesen Ergebnissen wird in Kenntnis der Pharmakokinetik von Digoxin beim Menschen auf eine gleiche biologische Verfugbarkeit des Digoxins aller drei untersuchter Medikamente geschlossen.

In 12 patients undergoing coloscopy, 0.5 mg digoxin in aqueous alcoholic solution was injected into the transverse colon. The late maximum of the blood level curve at about 2 hours after the administration suggested delayed absorption of the glycoside. However, the 24 hour urinary excretion of 17 +/- 3.4% in 8 patients with normal colonic mucosa demonstrated extensive absorption in the distal part of the bowel. The results have been contrasted with the findings in 4 patients with ulcerative colitis who excreted only 1.66 +/- 0.6% of the given dose in 24 hours.

Acetaminophen is a widely prescribed analgesic/antipyretic metabolized by hepatic glucuronide and sulfate conjugation. Twelve patients, 30-66 years of age, with stable Class III or IV congestive heart failure (CHF) and 12 healthy controls matched for age, sex, and weight received single 650-mg intravenous doses of acetaminophen. Pharmacokinetic variables were determined from multiple plasma acetaminophen concentrations measured by liquid chromatography during 12 h after the dose. Compared with controls, mean total clearance of acetaminophen was reduced in CHF patients (3.56 vs. 4.59 ml/min/kg, p less than 0.025), indicating reduced biotransformation capacity in this disease. Volume of distribution was also significantly reduced in CHF patients (0.85 vs. 1.02 L/kg, p less than 0.05). Since elimination half-life depends on both volume of distribution and clearance (both of which were reduced), the half-life was similar between groups (2.87 vs. 2.34 h, NS). Thus, hepatic conjugation of acetaminophen is impaired in CHF. The finding may also apply to other drugs biotransformed by conjugation.

Nine healthy volunteers received single 0.25, 0.5, 1.0, 1.5, and 2.0 mg doses of oral digoxin tablets in random sequence on five occasions separated by at least 4 weeks. Urinary excretion of immunoassayable digoxin was determined from 8 consecutive 24 h urine samples collected after each dose. Mean values of cumulative urinary excretion of digoxin at the 5 doses were: 40.9, 35.6, 36.4, 34.1, and 33.5% of the dose (F = 0.64; d.f. = 4.32; N.S.). Mean values of urinary excretion half-life were: 2.48, 2.03, 2.20, 2.07, and 1.87 days (F = 2.87; d.f. = 4.32; p = 0. 05). Thus, the bioavailability of orally administered digoxin tablets in healthy volunteers is dose-independent over an 8-fold range of doses.

infarction is not known. Moreover, the diagnosis of this arrhythmia should not be restricted to instances where delayed repolarization or extreme bradyarrhythmias are present. The therapeutic implications of this finding are unclear. Antiarrhythmic agents which potentially prolong the QT interval may be relatively contraindicated in this setting and the use of bretylium or early ventricular pacing may be preferable.

A LARGE and clinically important interaction between digoxin and quinidine is now well documented.1 2 3 4 5 The cardiac glycoside digitoxin is extensively used in clinical practice, but its interaction with quinidine has not been definitively evaluated.6 , 7 In this study, which assessed the pharmacokinetic interaction of digitoxin with quinidine, we found that simultaneous administration of quinidine had no statistically significant effect on the distribution or clearance of intravenously administered digitoxin. Methods Ten healthy male and female volunteers participated after giving informed consent (Table 1). Their ages ranged from 23 to 32 years. None had evidence of medical disease, and none were taking medications . . .

8 healthy volunteers (age 25±4 years) received in randomized sequence 50, 100, 200, 400, and 600 mg Atenolol orally and 50 mg Atenolol intravenously during 5 minutes under continuous ECG monitoring. On 3 consecutive days prior to the first application of Atenolol the volunteers were exercised on the treadmill under continuous measurement of the blood-pressure until a heart rate of 150 min was achieved. This individually determined load was used on the treadmill 3 h after oral and 1 hour after i.v.-application of Atenolol. Systolic and diastolic blood pressure and heart rate was measured at rest and after 1.5 min and 3 min of exercise. The results are expressed as difference between rest (=0) and exercise in blood pressure (Δs=systolic2 1Δd=diastolic RR in mm Hg) and heart rate (HR in min).

The influences of cimetidine and ranitidine on single-dose ibuprofen kinetics were evaluated. Thirteen healthy subjects took a single, 600 mg oral dose of ibuprofen on three occasions: in the control state without drug coadministration; during concurrent dosing with cimetidine, 1.2 gm/day; and during concurrent dosing with ranitidine, 150 mg twice daily. Compared with the control state, cimetidine increased the peak serum ibuprofen concentration (64 vs. 56 micrograms/ml), but the value during ranitidine dosing (57 micrograms/ml) was indistinguishable from the control value. There were no significant differences between control, cimetidine, and ranitidine conditions in ibuprofen elimination t1/2 (2.1, 2.1, and 2.0 hours, respectively). Overall there was a significant difference among the control, cimetidine, and ranitidine conditions in ibuprofen oral clearance (52.8, 48.3, and 54.1 ml/min, respectively), but individual differences in cimetidine vs. control and between ranitidine vs. control were not statistically significant. The impairment of ibuprofen clearance by cimetidine is small, and ranitidine had no detectable effect on ibuprofen kinetics. These findings should be further validated during chronic dosing with ibuprofen.

27 male volunteers aged 20 to 91 years, and 13 female volunteers aged 21 to 33 years, received single 5 to 10 mg doses of diazepam intravenously. Diazepam pharmacokinetics were determined from concentrations measured in multiple plasma samples drawn during 7 days after each dose. Diazepam elimination half-life among males (mean: 66 h) increased significantly with age (r = 0.53, p less than 0.005). Volume of distribution (mean: 1.39 liters/kg) also increased significantly with age (r = 0.67, p less than 0.001). Clearance of total diazepam in males (mean: 0.42 ml/min/kg) tended to decline with age (r = 0.32), but the association was of borderline significance (p = 0.1). Diazepam was extensively bound to plasma protein, with a mean free fraction among male subjects of 1.34%. Free fraction tended to increase with age (r = 0.14). Correction of volume of distribution and clearance for individual differences in binding did not alter the conclusions. Compared to young males, young females had larger volumes of distribution (1.87 vs. 1.34 liters/kg) and higher total clearance (0.63 vs. 0.49 ml/min/kg). These differences were even greater after correction for sex-related changes in protein binding. Elimination half-life did not differ between sexes. Since both age and sex can influence diazepam disposition, both should be considered as independent variables in studies of diazepam pharmacokinetics.

Alterations in drug metabolizing capacity associated with the aging process can be elucidated using analgesic-antipyretic agents as model compounds. Antipyrine serves to profile drug oxidizing capacity. Drug oxidation is significantly impaired in old age, but agerelated changes are far greater in men than in women. Acetaminophen analogously serves to profile conjugating capacity, which is minimally influenced by age both in men and in women. Changes in the capacity to biotransform these model compounds are reasonably well predictive of parallel changes in the same person's ability to metabolize other drugs transformed by the same pathway.

The kinetics of a single 1200 mg oral dose of oxaprozin, a nonsteroidal antiinflammatory agent of the propionic acid class, was studied in 22 healthy female volunteers aged 21 to 64 years. Eleven subjects had been taking a conjugated estrogen preparation for at least 3 months; the other 11 subjects served as control women who were not taking conjugated estrogens. Mean pharmacokinetic variables in control and conjugated estrogen groups were: volume of distribution, 15.1 vs 14.1 l; elimination half-life, 59.8 vs 54.2 h; clearance, 3.2 vs 3.1 ml/min; peak plasma concentration, 84.8 vs 90.7 micrograms/ml, respectively. None of the differences were significant. However, the time of peak concentration (8.9 vs 4.0 h) was significantly longer in the control group than in the conjugated estrogen group, respectively (p less than 0.05). Oxaprozin clearance, accomplished by a combination of oxidation and conjugation, is unimpaired by coadministration of conjugated estrogens.

The relation of serum digoxin concentrations (SDC) to subjective manifestations of toxicity was evaluated in 300 patients with permanent transvenous pacemakers. All had been receiving the same daily d

Concentrations of diazepam (DZ) and desmethyldiazepam (DMDZ) were determined quantitatively in the brain, skeletal muscle, heart, liver, lung, fat, adrenal gland, and kidney in 14 autopsied patients who had been treated with DZ or clorazepate (a DMDZ prodrug) during their hospital course. To facilitate interpatient comparisons, all tissue concentrations from the same patient were normalized as ratios to the concentration of DZ or DMDZ found in that patient's skeletal muscle. Tissue uptake ratios were not influenced by gender or chronicity of dosage. Distribution equilibrium was reached in at least two hours. Tissue uptake ratios differed considerably among tissues for DZ and DMDZ. Mean (+/- SE) DZ uptake ratio was highest for adrenal gland (12.1 +/- 5.9), liver (5.9 +/- 1.9), heart (4.3 +/- 1.0), and kidney (4.0 +/- 1.0), with lower values for lung (2.1 +/- 0.5), fat (2.2 +/- 0.4), and brain (1.9 +/- 0.4). Similar patterns were observed for DMDZ, except for significantly lower fat uptake. Extrapolating to an average body composition for a 70 kg man with 16% body fat, the largest fractions of total body stores of DZ would be found in muscle (42%), fat (35%), and liver (12%), with smaller stores in brain (4.3%), lung (3.3%), heart (1.7%), kidney (2.0%), and adrenal gland (0.24%).

Nine healthy men received 0.5, 1.0, and 1.5 mg digoxin intravenously in random sequence on occasions separated by at least 4 wk. Digoxin concentrations were measured in serum samples drawn during 36 hr after each dose, and a mean across-dose kinetic profile was determined for each subject. After a 6-mo washout period, the same subjects received 0.25 mg digoxin intravenously every 24 hr for 10 consecutive days. Samples were drawn every 12 hr during the first 9 days and at multiple points during 72 hr after the last dose. Mean kinetic variables for the single- and multiple-dose trials were as follows: elimination half-life (t½), 27.9 and 38.0 hr (r = 0.62); volume of distribution, 5.5 and 7.4 l/kg (r = −0.56); total clearance, 2.50 and 2.49 ml/min/kg (r = 0.19); urinary excretion t½, 40.9 and 37.9 hr (r = −0.14). Mean observed and predicted predose steady-state serum concentrations were 0.59 and 0.79 ng/ml (r = −0.02). Mean values of accumulation and elimination t½ were nearly identical (27.8 and 27.9 hr), but were not positively correlated (r = −0.64). Multiple-dose digoxin therapy leads to no systematic change in digoxin clearance. Single-dose kinetics is poorly predictive of the rate and extent of drug accumulation and of washout kinetics during and after multiple-dose therapy. Clinical Pharmacology and Therapeutics (1980) 28, 340–345; doi:10.1038/clpt.1980.171

Ten healthy volunteers received 300 mg. of quinidine base as the gluconate salt by 15-minute intravenous infusion. Physiologic variables monitored before, during, and for 24 hours after the infusion were: electrocardiogram, systolic and diastolic blood pressure, echocardiogram, and carotid pulse tracing. During quinidine infusion, mean ventricular rate increased by 18% (67.1 to 79.5 beats per minute) and corrected QT interval increased by 54% (0.44 to 0.68 sec.). QRS duration did not change significantly, nor did systolic or diastolic blood pressure. Ejection fraction (EF) measured by echocardiography did not decrease during quinidine infusion, but rather increased by 12% (0.58 to 0.65). Mean rate of circumferential fiber shortening (Vcf) likewise increased by 22%, from 1.15 to 1.40 per second. Over the 24-hours post-infusion, all monitored physiologic variables fluctuated considerably; in the case of EF and Vcf, apparently random variations over time were as great as those attributable to quinidine infusion. Mean (and range) kinetic variables for quinidine were: volume of distribution, 2.03 (1.47 to 3.00) liter/Kg.; elimination half-life, 6.3 (4.8 to 7.9) hours; total clearance, 3.8 (2.8 to 5.2) ml./min./Kg. Neither total nor unbound serum quinidine concentrations were significantly correlated with physiologic changes. Thus, intravenous quinidine in the doses studied did not have negative inotropic effects in a series of healthy humans.

Serum nifedipine concentrations and hemodynamic changes were evaluated in ten healthy volunteers after a single 40-mg oral dose of nifedipine. Peak serum concentrations averaged 45 micrograms/l, attained 2.7 h after dosage. The mean elimination half-life was 5.9 h (range: 3-12 h). Blood pressure, ventricular rate, and echocardiographically-determined rate of circumferential fiber shortening did not differ between placebo and nifedipine trials. Five additional subjects ingested nifedipine once in the control state and on a second occasion with a standard breakfast. Coingestion of food delayed the peak serum nifedipine concentration but did not alter the area under the serum concentration curve. Thus the pharmacokinetic profile of nifedipine indicates that a three- or four-times-daily dose is, in general, appropriate in clinical practice. Completeness of absorption is not altered by coadministration with food. Adverse hemodynamic effects of single oral doses in healthy persons are not evident.

5 patients with chronic renal failure on maintenance hemodialysis and 5 healthy matched controls received single 20-mg intravenous doses of clorazepate dipotassium. Clearance of pharmacologically active unbound desmethyldiazepam was reduced in renal failure patients as opposed to controls, and free fraction in serum was greater. Since desmethyldiazepam distribution was reduced in renal patients, elimination half-life was actually shorter than in controls (36 vs. 57 h). In 10 dialysis patients receiving chronic diazepam treatment (5-15 mg/day), steady-state concentrations of diazepam (56 ng/ml) and desmethyldiazepam (77 ng/ml) were significantly lower than in age- and weight-matched controls receiving similar doses (189 and 216 ng/ml, respectively). However after correction for the higher free fractions of both compounds in renal patients as opposed to controls, steady-state concentrations of unbound drug were found to be similar between groups. Interpretation of kinetic variables and steady-state serum concentrations of extensively protein-bound drugs requires consideration of alterations in protein binding that may occur in disease states.

Ten healthy volunteers received a single 10 mg intravenous dose of the 5-hydroxytryptamine-2 serotonin antagonist ketanserin in the control state and again during coadministration of propranolol, 80 mg b.i.d. There were no differences between control and propranolol treatment conditions in ketanserin volume of distribution (5.2 vs. 3.8 L/kg), elimination half-life (6.6 vs. 4.7 hours), clearance (9.7 vs. 10.0 ml/min/kg), or 72-hour excretion of intact ketanserin (0.7% vs. 0.7% of dose) or ketanserinol (21.8% vs. 24.9% of dose). In a second study, eight volunteers received a 160 mg oral dose of propranolol hydrochloride in the control state and again during treatment with ketanserin, 40 mg b.i.d. There were no significant differences between control and ketanserin conditions in the time of peak serum propranolol concentration (2.1 vs. 1.5 hours after dosage) or elimination half-life (3.8 vs. 4.1 hours). However, ketanserin increased peak serum propranolol concentrations (169 vs. 233 ng/ml) and reduced oral clearance (39 vs. 27 ml/min/kg); the differences were not statistically significant (0.05 less than P less than 0.1) with a sample size of eight. Thus therapeutic doses of propranolol in healthy volunteers do not alter the kinetics of a single dose of ketanserin. Therapeutic doses of ketanserin may impair oral clearance of propranolol, leading to increased area under the serum concentration curve and higher peak serum levels.

The elimination of quinidine is accomplished by a combination of renal excretion of the intact drug (15 to 40% of total clearance) and hepatic biotransformation to a variety of metabolites (60 to 85% of total clearance). Many of the metabolites appear to be pharmacologically active. Typical ranges for kinetic properites of quinidine in healthy persons are: apparent volume of distribution 2.0 to 3.5 litres/kg; elimination half-life 5 to 12 hours; clearance, 2.5 to 5.0 ml/min/kg. Quinidine clearance is reduced in the elderly, in patients with cirrhosis, and in those with congestive heart failure. Oral quinidine is available either as relatively rapidly absorbed conventional tablets (usually quinidine sulphate) or as a variety of slowly absorbed sustained release preparations. Absolute systemic availability generally is 70% or greater. Quinidine is 70 to 95% bound to plasma protein, primarily to albumin but also to a number of other plasma constituents. Binding is reduced in patients with cirrhosis, partly because of hypoalbuminaemia, but is not influenced by renal insufficiency. Clinical interpretation of total serum or plasma quinidine concentrations must be altered in patients with reduced or increased binding, since it is the unbound fraction which is pharmacologically active.

Flurazepam and three of its metabolic products (desalkyl, hydroxyethyl, and aldehyde metabolites) can be simultaneously quantitated without derivatization by gas chromatography with electron capture detection. After addition of a suitable internal standard, unknown biological samples and calibration standards are extracted at neutral pH into benzene/isoamyl alcohol. The reconstituted extract is chromatographed at 275 degrees C with a 10% OV-101 liquid phase, which allows resolution of all 5 compounds. In some cases a 1% OV-225 liquid phase is used for quantitation of hydroxyethylflurazepam. The method is sufficiently sensitive and reproducible for use in clinical and experimental pharmacokinetic studies.

Dikalium-Chlorazepat wird nach oraler Gabe im Magen durch saureabhangige Hydrolyse und Dekarboxylierung zu Desmethyldiazepam umgewandelt. In fruheren Studien konnte gezeigt werden, das Natriumbicarbonat und Antazida Ausmas und Geschwindigkeit der Resorption von Desmethyldiazepam signifikant erniedrigen [1, 2]. Da Erkrankungen mit einer Verminderung der Magensaure eine ahnliche Wirkung ausuben konnen [3], haben wir den Einflus einer Magenresektion nach Billroth auf die Desmethyldiazepam- Absorption untersucht und die Ergebnisse mit denen einer jungen und alteren Kontrollgruppe verglichen.

The kinetics of single 30-mg oral doses of oxazepam were determined in 22 male and nine female volunteers aged 20-86 years. Oxazepam plasma concentrations were measured in multiple plasma samples drawn during 36 h after each dose. Mean kinetic variables in males and females, respectively, were: elimination half-life, 7.5 and 8.5 h; volume of distribution, 0.96 and 1.17 l/kg; clearance, 1.48 and 1.70 ml/min/kg. Sex differences were not significant, nor were any of the kinetic variables significantly related to age. However, oxazepam clearance increased significantly with heavier cigarette smoking (r = 0.48, p less than 0.01). Mean clearance in smokers (1.98 ml/min/kg) was significantly higher than in nonsmokers (1.23 ml/min/kg, p less than 0.01). Thus, smoking is a more important determinant of oxazepam clearance than age or sex.

The pharmacokinetics of high-dose i.v. diazepam were studied in two patients in an intensive care unit. The first patient received up to 240 mg of diazepam daily for 21 days while the second received 60 mg daily for 30 days. Plasma concentrations of diazepam and its major metabolite, desmethyldiazepam, were very large but, despite severe underlying disease and simultaneous administration of several other drugs, the half-lives of diazepam and desmethyldiazepam washout were consistent with those found in healthy persons. Washout half-lives in the first patient were, if anything, shorter than expected, possibly caused by simultaneous administration of phenobarbitone. Thus the kinetics of diazepam are apparently not altered by administration of large doses.

Seit kurzem ist bekannt, das Propranolol (P) die Pharmakokinetik anderer Arzneimittel erheblich beeinflussen kann: So verlangert eine P-Therapie beim Menschen die Halbwertzeit von Antipyrin um mehr als 40% und vermindert die Anitipyrin- Clearance um 30%. Am Hund konnten Shand et al. zeigen, das die Lidocain-Clea- rance bei gleichzeitiger P-Gabe um 24% verringert und die HWZ um 48% verlangert wird. Wir haben daher untersucht, ob die Pharmakokinetik von i.v. appliziertem Chinidin sowie die durch Chinidin bedingten EKG-Veranderungen unter einer gleichzeitigen P-Gabe beeinflust werden.

Ten healthy volunteers ingested a single 18-mg oral dose of sustained release nitroglycerin (TNG) (Giulini-Pharma) on three occasions: once in the control state, once during coadministration of propranolol (80-mg three times daily), and once during coadministration of metoprolol (100-mg twice daily). The degree of beta adrenergic blockade was evaluated by the metaproterenol infusion test. Plasma concentration of TNG and its major metabolite, 1,2-dinitroglycerin (DNG), during 12 h after each dose were measured by gas chromatography-mass spectrometry. Intact TNG was not detected in the plasma of any patient. The major metabolite, DNG, was easily measurable in blood, and had a biphasic plasma concentration profile. Coadministration of the beta-blockers had no influence on any of the kinetic variables for DNG. The mean values during control, propranolol, and metoprolol trials of DNG elimination half-life were: 1.35, 1.10, and 1.09 h; total area under the curve: 42, 38, and 42 ng/ml × h; oral clearance: 6.6, 7.2, and 6.4 liters/min. Thus TNG when administered as a sustained release oral preparation is rapidly and completely transformed to DNG. There was no pharmacokinetic interaction between sustained release TNG and two commonly used beta-blocking agents, suggesting that any clinical interaction that may-occur between sustained release nitroglycerin and beta-blocking agents is pharmacodynamic rather than pharmacokinetic in nature.

The pharmacokinetics and dynamics of the D- and L-isomers of the beta-adrenergic blocking agent penbutolol were investigated in healthy human volunteers. In Study One, subjects received a single 40-mg oral dose of L-penbutolol (the pharmacologically active stereoisomer), and matching placebo on two occasions. A mean peak serum penbutolol concentration of 268 ng/ml was reached at 0.9 h after dosing. Elimination half-life averaged 1.6 h, and total clearance 16.6 ml/min per kg body weight. Changes in blood pressure, ventricular rate, and rate of circumferential fiber shortening (Vcf) did not differ between L-penbutolol and placebo. In Study Two, subjects received 40 mg D-penbutolol, L-penbutolol, and placebo on three occasions. Total clearance of D-penbutolol was higher than for the L-isomer (43.7 vs 15.9 ml/min/kg; P less than 0.01); this was reflected in correspondingly increased area under the serum concentration curve for conjugates of the oxidized metabolite 4-hydroxy penbutolol (2.25 vs 0.66 micrograms/ml X h; P less than 0.005). In contrast, direct conjugates of L-penbutolol achieved higher serum concentrations than conjugates of D-penbutolol. Alterations in blood pressure, ventricular rate, and Vcf for D-penbutolol, L-penbutolol, and placebo were quantitatively small. Thus the clearance of penbutolol after oral administration in humans is stereoselective, but the oxidative pathway is more stereosensitive than the parallel conjugative pathway. Penbutolol causes minimal alterations in parameters of cardiac function after single 40-mg doses in healthy humans.

Pharmacokinetics of the benzodiazepine bromazepam were evaluated in volunteer subjects who received single 6 mg oral doses followed by blood sampling during the next 48 hours. Age and gender effects were studied in 32 subjects, divided into young (aged 21 to 29 years) and elderly (aged 60 to 81 years) groups. Compared with young subjects, the elderly had significantly higher peak serum bromazepam concentrations (132 vs. 82 ng/ml), smaller volume of distribution (0.88 vs. 1.44 L/kg), lower oral clearance (0.41 vs. 0.76 ml/min/kg), and increased serum free fraction (34.8% vs. 28.8% unbound). However, gender had no significant influence on bromazepam kinetics. In 11 young female users of oral contraceptive steroids, compared with seven age- and weight-matched control women not using oral contraceptives, no differences in bromazepam kinetics were observed. Coadministration of cimetidine (1.2 gm daily) significantly reduced bromazepam clearance (0.41 vs. 0.82 ml/min/kg) and prolonged elimination half-life (29 vs. 23 hours). Propranolol (160 mg daily) significantly prolonged bromazepam half-life (28 vs. 23 hours), but the reduction in clearance associated with propranolol (0.65 vs. 0.82 ml/min/kg) did not reach significance. Bromazepam has the pharmacokinetic characteristics of benzodiazepines with half-life values between 20 and 30 hours. Consistent with its biotransformation pathway by hepatic microsomal oxidation, bromazepam clearance is significantly impaired in elderly individuals, by coadministration of cimetidine and possibly propranolol.

Nine healthy male volunteers received single 0.5, 1.0, and 1.5 mg. doses of intravenous digoxin in a randomized three-way crossover study. Multiple venous blood samples were drawn during 35 hours after each dose, and all urine was collected for 6 consecutive days. Concentrations of digoxin in serum and urine were determined by radioimmunoassay. Over-all mean values for kinetic variables were: distribution half-life, 0.35 hours; elimination half-life, 27.9 hours; volume of distribution, 5.46 liters/Kg; total clearance, 2.51 ml./min./Kg. The mean projected cumulative urinary excretion of digoxin was 70.1% of the dose; mean renal clearance of digoxin was 1.71 ml./min./Kg., not significantly different from creatinine clearance (1.50 ml./min./Kg.). None of the identifiable pharmacokinetic variables was significantly influenced by dose, suggesting that digoxin disposition is dose-independent in healthy individuals.

Five medically stable male patients with cirrhosis and four healthy age- and sex-matched controls received single 5-mg oral doses of diazepam (DZ) daily for 22 consecutive days. Plasma concentrations of DZ and its major metabolite desmethyldiazepam (DMDZ) were measured daily during the period of dosing and in the 7-day washout period that followed. Clinical self-ratings of sedation, fatigue, mood state, and sleep patterns were obtained daily during the period of dosage with the use of visual analogue scales. Steady-state plasma DZ concentrations were higher (165 and 98 ng/ml), and DMDZ concentrations tended to be higher (399 and 206 ng/ml), in cirrhotics than in controls. Increases in self-rated daytime sedation also were greater in cirrhotics than in controls and correlated strongly with total DZ and DMDZ plasma concentration during the first 2 wk of diazepam dosing. Thus, reduced clearance of DZ in cirrhotics leads to increased cumulation during long-term dosing. This in turn is associated with increased clinical sedation. Sedative effects are partly offset as treatment proceeds because of adaptation or tolerance. Based on kinetic findings, diazepam can be given safely to cirrhotic patients provided daily dosage is reduced by approximately 50%. Clinical Pharmacology and Therapeutics (1983) 33, 471–476; doi:10.1038/clpt.1983.64

Anesthetized dogs received a single 1.0-mg/kg intravenous dose of flurazepam hydrochloride, following which multiple blood and cerebrospinal fluid (CSF) samples were taken over the next 8 h. Concentrations of flurazepam and its metabolite, desalkylflurazepam, were determined by gas chromatography with electron-capture detection. Mean kinetic variables for flurazepam were: volume of distribution 7.9 l/kg, elimination half-life 2.3 h, clearance 37 ml/min/kg, serum free fraction 25% unbound. The metabolic product desalkylflurazepam appeared in serum in low concentrations, and was eliminated with a half-life of 4.9 h. Flurazepam rapidly entered CSF, then was eliminated in parallel with flurazepam in serum. However, the extent of entry into CSF was limited, with the mean ratio of area under the curve for CSF versus serum (0.24) nearly identical to the serum free fraction. Thus, intravenous flurazepam in dogs is characterized by extensive distribution, high clearance, and short half-life. Entry into CSF is rapid, and appears governed by passive diffusion. The extent of CSF entry is limited by protein binding in serum.

Ten healthy volunteers aged 22 to 30 years received a single 20-mg oral dose of temazepam. Serum temazepam concentrations were measured by gas chromatography at multiple times during the next 48 hours. Mean kinetic variables were: volume of distribution, 1.45 liter/kg; elimination half-life, 8.6 hours; total clearance, 2.33 ml/min/kg. The subjects then received 20 mg temazepam once daily for seven consecutive days. Serum concentrations were measured just prior to each dose and at multiple time points after the last dose. Predose serum levels increased during the first three days of dosage, then increased no further. Mean values measured 24 hours after doses 1 through 6, respectively, were 33, 43, 55, 47, 53, and 51 ng/ml. Based on the area under the serum concentration curve after the last dose compared with that after the first dose, the mean accumulation ratio was 1.32, which was significantly greater than unity. The extent of accumulation was consistent with that predicted from the single-dose study. Postdosage washout half-life averaged 10.2 hours. Thus, temazepam has a pharmacokinetic profile of an intermediate half-life benzodiazepine that produces an intermediate degree of accumulation with multiple dosage.

The kinetics of diazepam absorption were assessed in 37 healthy volunteers, aged 19--79 years, who ingested a single 5-mg tablet in the fasting state. Diazepam plasma concentrations were measured by gas chromatography in multiple samples drawn over the next 72 hr. After a lag time averaging 12 min elapsed between tablet ingestion and the start of absorption, first-order absorption proceeded with a mean half-life of 19 min (range: 0--96 min), with peak plasma concentrations reached 0.9 hr after dosage (range: 0.25--2.5 hr). Age and sex did not influence absorption kinetics. Peak plasma concentrations averaged 157 ng/ml, and tended to be higher in women than in men because of lower body weights in women. Peak levels also declined with age, probably due to increased volume of distribution of diazepam in the elderly. Absolute systemic availability of oral diazepam was evaluated in seven of the subjects who received intravenous diazepam on another occasion. Based on areas under the oral versus intravenous plasma concentration curve, bioavailability of diazepam averaged 97%. Six male patients, at least 2 years after undergoing Billroth gastrectomy, also participated in the diazepam absorption study. Absorption kinetic parameters were nearly identical to those in six healthy age-matched male volunteers without gastrointestinal disease. Thus absorption of oral diazepam in the fasting state is rapid and nearly complete, and is minimally influenced by age, sex, or Billroth gastrectomy.

Salicylate kinetics following single, 650-mg intravenous and oral doses of aspirin were evaluated in humans in 2 studies. Complete conversion of aspirin to salicylate was assumed. The first study involved 25 young (25-40 years) and 21 elderly (66-89 years) healthy male and female volunteers. Mean salicylate clearance was lower in elderly females compared with that in young females; however, the difference between young men and elderly men was not significant. Salicylate free fraction in plasma increased significantly with age in men and women. After correction for free fraction, unbound mean clearance was reduced in elderly men compared with young men, and in elderly women compared with young women. Peak plasma salicylate concentrations after taking oral aspirin were not significantly influenced by age, and systemic availability of salicylate in all groups was complete. The second study compared 20 obese subjects (mean weight 113 kg) with 20 normal weight controls (mean weight 67 kg) matched for age, sex, height, and smoking habits. Small differences between obese and control groups were observed in total salicylate volume of distribution (Vd), unbound Vd, and mean clearance of total or unbound salicylate. Following normalization for total weight, however, values of total Vd and mean clearance were significantly smaller in obese subjects than in normal weight subjects. Rate and completeness of salicylate absorption were not influenced by obesity when aspirin was ingested, although peak levels were lower in obese subjects. If applied to multiple doses, the reduced unbound clearance of salicylate in the elderly would imply increased accumulation unless doses are appropriately adjusted downward. During long-term therapy, salicylate dosage for obese individuals should not be adjusted upward in proportion to total weight.

The bioavailability of a single 250-mg oral dose of tetracycline hydrochloride was studied in seven patients following Billroth-II gastrectomy in comparison with seven control subjects matched for age and body weight. There were no significance differences between control subjects and gastrectomized patients in the apparent lag time prior to the start of absorption (23.6 vs. 22.8 min), peak serum tetracycline concentration (1.72 vs. 1.75 microgram/ml), the time of attainment of peak concentrations (3.35 vs. 3.42 hr), the apparent first-order absorption half-life (1.8 vs. 1.4 hr), or the apparent first-order elimination half-life (8.0 vs. 8.7 hr). Completeness of tetracycline absorption, as judged by area under the 24-hr serum concentration curve, did not differ significantly between the two groups, nor did 24-hr urinary excretion of tetracycline. Thus the abnormalities of gastrointestinal structure and function produced by Billroth-II gastrectomy do not result in impairment of the rate and completeness of tetracycline absorption.

Nach i.v.-Infusion von 20 mg bei 6 Probanden fallt die Blutspiegelkurve zunachst rasch, im Sinne einer einfachen Exponentialen mit einer Halbwertzeit von 5.3±0.3 h ab. Dieser Wert ist erheblich langer als von Shand u. Mitarb. mit der fluorimetri- schen Methode bestimmt, und past auch sehr viel besser zu dem, was wir aus der Klinik uber das Abklingen der Betablockade wissen. Die Kurve lies sich durch eine entsprechende rechnerische Angleichung am besten durch die Summe zweier Expo- nentialterme beschreiben, so das ein Zweikompartimentmodell angewandt werden konnte. Die totale Clearance lies sich mit 380±30 ml/min berechnen. Das relative Verteilungsvolumen, berechnet aus der i.v.-Kurve, betragt 2.6±0.4 1/kg. Das bedeutet, das Propranolol in erheblichem Ausmas im Gewebe gespeichert wird. Nach oraler Verabreichung von 80 mg kam ein rascher Blutspiegelanstieg zur Darstellung, die Kurve erreichte nach etwa 3 h ihr Maximum und fiel dann ahnlich wie die i.v.-Kurve ab. Bei der Angleichung fiel auf, das die Invasion nicht linear verlauft, das uberrascht insofern, als bisher auch dieses Phanomen nicht beschrieben wurde. Aussagen uber die biologische Verfugbarkeit sind aus den hier dargestellten Experimenten nicht moglich, da bei der oralen Gabe eine grosere Dosis verabreicht wurde und die Resorption von Propranolol dosisabhangig ist.

Forty healthy men and women 19 to 80 years old received a single 10 mg oral dose of the 7-nitro benzodiazepine nitrazepam. Nitrazepam plasma concentrations were measured during the next 72 hours. Among men, the elderly had a larger volume of distribution (Varea) than did younger subjects (1.96 vs. 1.63 L/kg; P < 0.05); because clearance did not change with age (0.84 vs. 0.95 ml/min/kg), the prolonged t½ in elderly men (28 vs. 20 hours; P < 0.01) was a result of the larger Varea. Elderly and young women did not differ in nitrazepam Varea (2.58 vs. 2.55 L/kg), t½ (26 vs. 27 hours), or total clearance (1.19 vs. 1.09 ml/min/kg). The nitrazepam free fraction in plasma (18% to 19% unbound) was not related to age or sex. Among 18 subjects who also received antipyrine, the clearance of nitrazepam and antipyrine were not correlated (r = 0.23). Thus age minimally influences nitrazepam clearance (accomplished mainly by nitroreduction), which in turn is not significantly related to antipyrine oxidizing capacity. Clinical Pharmacology and Therapeutics (1985) 38, 697–703; doi:10.1038/clpt.1985.248

Plasma midazolam concentrations following single therapeutic doses can be quantitated using electron-capture gas-liquid chromatography. After addition of a benzodiazepine analogue as an internal standard, samples are extracted with benzeneisoamyl alcohol (98.5:1.5). The organic extract is evaporated to dryness, reconstituted, and chromatographed on an SP-2250 liquid phase. The automatic sampler allows up to 100 chromatographic analyses per 24-h period. The sensitivity limits are 2-3 ng of midazolam per ml of plasma, and the variation of identical samples is 7 per cent or less. The method was used in a study of six females who received single intravenous doses of midazolam for purposes of anesthetic induction prior to minor gynecologic procedures. Mean (+/- SE) kinetic variables for midazolam were: volume of central compartment, 0.37 (+/ 0.06 l/kg; total volume of distribution, 1.72 (+/- 0.05) l/kg: initial distribution half-life, 7.2 (+/- 1.6) min; elimination half-life, 2.5 (+/- 0.2) h; total clearance, 8.1 (+/- 0.52) ml.min-1.kg-1.

Drug Monitoring bedeutet die Uberwachung der Therapie durch die Messung des Blutspiegels. Als diese Moglichkeit vor mehr als 10 Jahren erstmalig ins Auge gefast wurde, war die Blutspiegelmessung noch hochspezialisierten Laboratorien vorbehalten, denn die Untersuchungen erforderten besonders qualifiziertes Personal und teure Gerate. Wegen der geringen vorhandenen Erfahrung konnten wir in der Klinik mit erhaltenen Werten noch wenig anfangen. Heute verfugen wir uber relativ einfache analytische Methoden fur nahezu alle wesentlichen Medikamente (1). Unser Verstandnis der Pharmakokinetik ist soweit fortgeschritten, das wir aus den erhaltenen Konzentrationen sinnvolle Konsequenzen ziehen konnen, und es bestehen ausreichende Erfahrungen uber den therapeutischen Plasmaspiegelbereich der meisten Medikamente. Diese Entwicklung hat die Methode des Drug Monitoring gefordert, haufig aber auch zu einer unkritischen Verwendung gefuhrt.

A single oral dose of doxylamine succinate 25 mg was administered to 21 young (20 to 43 years) and 22 elderly (60 to 87 years) volunteers. Multiple plasma doxylamine concentrations were determined during a 30-hour period after each dose. Elderly and young women did not differ significantly in peak plasma doxylamine concentration (Cmax) [116 vs 103 micrograms/L], time to Cmax (tmax) [2.4 vs 2.4 h], elimination half-life (12.2 vs 10.1 h), volume of distribution (179 vs 176 L) or clearance (191 vs 218 ml/min). Cmax (107 vs 108 micrograms/L) and tmax (2.1 vs 1.6 h) also did not differ between elderly and young men. However, elderly men had reduced doxylamine clearance (174 vs 240 ml/min, p less than 0.02; 2.5 vs 3.2 ml/min/kg, p less than 0.07) and prolonged half-life (15.5 vs 10.2 h, p less than 0.05). The reduced doxylamine clearance and prolonged half-life in elderly men, but not in elderly women, is similar to results for many other drugs which are transformed by oxidation.

Interaktionen des sympathischen und parasympathischen Nervensystems sind vielfaltig und komplexer Natur. Wir haben untersucht, in welchem Ausmas das parasympathische Nervensystem die inotropen Wirkungen sympathomimetischer Amine (Dobutamin, Dopamin, Norepinephrin, Isoproterenol) modifiziert ( 1-5).

5 healthy volunteers received 4–5 mg/kg of quinidine base by 15-min intravenous infusion on two occasions separated by at least 1 week. Multiple venous blood samples and all urine was collected during the 48 h after each dose and were analyzed for concentrations of total and unbound quinidine (following separation by equilibrium dialysis) by a double-extraction spectrophotofluorometric technique. The first quinidine administration was a ‘control’; for the second quinidine administration, propranolol (40 mg orally every 4–6 h) was given, starting 12 h before the quinidine dosage and continuing for the the duration of the trial. A high degree of β-blockade, assessed by intravenous isoproterenol sensitivity, was achieved by propranolol treatment. Mean (± SE) kinetic variables for quinidine during control and propranolol trials, respectively, were: volume of distribution, 3.0 ± 0.5 versus 2.9 ± 0.5 1/kg (NS); elimination half-life, 7.8 ± 1.1 versus 7.6 ± 0.7 h (NS); total clearance, 4.5 ± 0.6 versus 4.3 ± 0.6 ml/min/kg (NS); renal clearance, 1.58 ± 0.2 versus 1.57 ± 0.2 ml/min/kg (NS); percent unbound, 23.0 ± 1.1 versus 23.6 ± 1.3% (NS). Intravenous quinidine produced tachycardia, T-wave flattening, and prolongation of the QT-interval; none of the changes were influenced by propranolol coadministration. Thus propranolol did not significantly alter the pharmacokinetics or acute electrocardiographic effects of intravenous quinidine in healthy volunteers.