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The influence of therapeutic doses of ibuprofen on the distribution and clearance of antipyrine in humans was evaluated in a series of healthy volunteers. Subjects received a single intravenous dose of antipyrine on two occasions, once in the drug-free control state and again during coadministration of ibuprofen, 1.6 to 2.4 Gm per day in divided doses. Compliance was verified by measurement of plasma ibuprofen levels, which averaged 22 micrograms/ml. Kinetic variables for antipyrine were determined from multiple plasma antipyrine concentrations measured during 24 hours after each dose. Between drug-free control and ibuprofen coadministration trials, there was no significant difference in antipyrine volume of distribution (0.69 vs. 0.69 liter/kg), elimination half-life (12.2 vs. 12.5 hours), or total metabolic clearance (0.69 vs. 0.70 ml/min/kg). Thus, ibuprofen does not impair the clearance of the marker compound antipyrine, often used as an index of drug oxidizing capacity in humans.

The influence of cimetidine on the pharmacokinetics of alprazolam and triazolam, two triazolobenzodiazepines metabolized by hepatic microsomal oxidation, was evaluated in a series of healthy volunteers. Subjects ingested single 1.0 mg dose of alprazolam or 0.5 mg doses of triazolam on two occasions, with and without concurrent administration of cimetidine (300 mg) every 6 h. For alprazolam, which has a low hepatic clearance and low extraction ratio, cimetidine significantly impaired total metabolic clearance (1.05 versus 1.66 ml/min/kg, P less than 0.005), resulting in significantly prolonged elimination half-life (16.6 versus 12.4 h, P less than 0.005). For triazolam, which has higher hepatic clearance and an intermediate extraction ratio, total clearance was reduced by cimetidine (3.9 versus 5.9 ml/min/kg), causing a significant increase in total area under the plasma concentration curve (25 versus 38 ng/ml X h, P less than 0.02). However, elimination half-life of triazolam was not influenced by cimetidine (3.3 versus 3.2 h), indicating that the reduction in clearance was manifested as increased systemic availability. Thus, cimetidine impairs the clearance of both alprazolam and triazolam, but the consequences of the kinetic change are different because of the differing hepatic extraction profiles of the two drugs.

The influence of obesity on the distribution or clearance of lorazepam and oxazepam, two benzodiazepines biotransformed by glucuronide conjugation, was studied in a series of obese subjects (mean weight 113 kg; mean percent IBW 179%) and healthy controls of normal body habitus matched for age and sex. Overweight subjects and controls received 2 to 3 mg of lorazepam intravenously or 30 mg of oxazepam orally. Absolute Vd in obese compared to control subjects was increased for both lorazepam (131 vs. 77 L, p less than 0.001) and oxazepam (97 vs. 38 L, p less than 0.001). When normalized to body weight, Vd/kg was similar for both drugs. Total metabolic clearance was similarly increased in the obese cohort for lorazepam (102 vs. 63 ml/min, p less than 0.005) and oxazepam (157 vs. 50 ml/min, p less than 0.001). Again, when normalized to body weight, clearance per kilogram was similar for both drugs. Since both Vd and clearance increased with body weight, elimination half-life (dependent on both Vd and clearance) was not significantly different in obese subjects (lorazepam 16.5 vs. 14.9 hr; oxazepam 7.7 vs. 8.9 hr). A random subgroup of obese and control subjects received a single intravenous dose of acetaminophen, also biotransformed by conjugation. Acetaminophen clearance was significantly correlated with that of lorazepam (r = 0.59, p less than 0.01) and oxazepam (r = 0.87, p less than 0.001), and clearance of LRZ and OXZ were similarly intercorrelated (r = 0.72, p less than 0.01). Thus obesity is associated with enhanced capacity for biotransformation of drugs via glucuronide conjugation. conjugating capacity increases in proportion to TBW and is consistent among drugs biotransformed by this mechanism.

Reports of unusual increases in transformation frequency in low density cultures of C3H/10T1/2 cells suggest that transformation occurs via an indirect multistage mechanism. The effect of surviving cell density upon subsequent focus production was examined in C3H/10T1/2 cultures treated with acetone, 12-O-tetradecanoylphorbol-13-acetate (TPA), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), MNNG plus TPA, or 3-methylcholanthrene (MCA). Foci developed independent of cell density in 0.5 and 5.9% of all cultures exposed to acetone and TPA (0.25 micrograms/ml), respectively. Transformation after treatment with MNNG (0.5 micrograms/ml) occurred with low frequency (less than or equal to 7 X 10(-4)/surviving cell) and was enhanced by TPA. In MNNG plus TPA treated cultures containing less than or equal to 140 viable cells the fraction of dishes with foci was dependent upon the number of cells present at the time of MNNG treatment. As a result, relatively constant frequencies of focus formation were obtained (less than or equal to 6 X 10(-3) after correction for focus formation in TPA treated solvent controls). Focus frequency declined at cell densities greater than or equal to 350 cells. In contrast, treatment with MCA (1.0 microgram/ml) produced transformed foci with frequencies that varied from 3.3 X 10(-2) at the lowest density (5.5 cells) to 5.4 X 10(-4) at the highest (4400 cells). In low density cultures (5.6-56 cells), the fraction of dishes with foci was independent of the number of cells treated. Thus cell density had differential effects upon the frequency of foci produced by MCA or MNNG plus TPA. However, binding studies demonstrated that 6-7% of the MCA added to cell culture dishes was retained after the termination of carcinogen treatment. This residual MCA possessed biological activity which may be sufficient to elevate transformation frequencies in low density cultures.

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.

Pharmacodynamics and disposition of diltiazem were determined in twelve young (30 to 39 years of age) and twelve elderly (65 to 83 years of age) persons with hypertension after they had received diltiazem by rapid intravenous and long-term oral administration. Plasma disappearance half-life of diltiazem increased similarly and significantly in both groups with long-term dosing (young: rapid intravenous, 3.7 +/- 0.8 hour; long-term oral, 6.3 +/- 1 hour [mean +/- SE]; elderly: rapid intravenous, 3.8 +/- 0.7 hour; long-term oral, 7.2 +/- 2.1 hour; p less than 0.01). During long-term therapy both systolic and diastolic blood pressure was significantly lowered from baseline beyond a 12-hour dose interval, with greater decreases in systolic blood pressure in the elderly. Heart rate was decreased with long-term therapy in both groups. Maximal prolongation of PR interval was greater in the young after the intravenous dose (young: 46 +/- 28 msec; elderly: 24 +/- 11 msec; p less than .01), but this effect was not seen with long-term therapy. These data demonstrate that diltiazem administered every 12 hours is an effective antihypertensive agent in both young and elderly patients.

Calcium antagonist drugs under clinical development are of the Type I (verapamil, diltiazem-like) and Type II (nifedipine-like) classes. Tiapamil, the only Type I drug currently available, is a high clearance, widely distributed drug which undergoes extensive presystemic elimination. Pharmacokinetically it is quite similar to verapamil; however, it does have increased biliary excretion and decreased binding to plasma proteins. Eight Type II (dihydropyridine) drugs are reviewed. Seven of these drugs (felodipine, isradipine, nicardipine, nilvadipine, nimodipine, nisoldipine and nitrendipine) are pharmacokinetically similar to nifedipine, with high clearance, extensive distribution, and significant presystemic elimination. Amlodipine has lower clearance, even greater peripheral distribution, and greatly decreased presystemic elimination. Three of the 8 dihydropyridines have been reported to have plasma protein binding greater than 90%. Unlike nifedipine, each dihydropyridine drug under development has an asymmetric centre; therefore each in fact is a racemic mixture. Human pharmacokinetic and pharmacodynamic data have not been reported for any of the racemates. Each of the drugs has been studied in patients with hepatic and renal disease. Predictably, patients with severe hepatic disease have decreased presystemic clearance and, in some cases decreased clearance after intravenous administration of the dihydropyridines, although renal failure has little influence on their pharmacokinetics. Unfortunately, disease-drug interaction studies of this class of drugs do not generally report plasma protein binding. The effect of age on the disposition of 2 of the dihydropyridines has been reported; however, only for nicardipine can a conclusion be drawn, namely that volume of distribution may increase with age and clearance may remain unchanged. A variety of potential drug-drug interactions have been evaluated, most commonly the effect of these drugs on cardiac glycoside disposition and effect, and the effect of cimetidine on the disposition of dihydropyridines. Tiapamil, like verapamil, impairs digoxin clearance significantly. Among the dihydropyridines, although minor pharmacokinetic effects have in some cases been reported, the magnitude of the interactions suggest they have limited clinical importance. From drugs currently under development, it is clear that a large number of calcium antagonists will soon be introduced into clinical use. Only 1 of the newer drugs, amlodipine, has significant pharmacokinetic differences from the agents currently in use, although possible pharmacodynamic differences among the drugs have been suggested.(ABSTRACT TRUNCATED AT 400 WORDS)

The influence of cimetidine coadministration, 300 mg every 6 hours, on the kinetics of single oral doses of oxazepam (30 mg), lorazepam (2 mg), and flurazepam (30 mg) was evaluated in healthy volunteers. Cimetidine had no significant effect on the peak plasma concentration or the time of peak concentration for either oxazepam, lorazepam, or desalkylflurazepam (formed from flurazepam). Cimetidine likewise did not alter the elimination half-life of oxazepam (9.4 hours) or lorazepam (11.6 hours), and did not change total AUC for lorazepam. Oxazepam AUC was increased an average of 10 per cent by cimetidine (P less than 0.02). In contrast, cimetidine prolonged desalkylflurazepam elimination half-life (141 vs. 94 hours, P less than 0.1) and increased AUC an average of 65 per cent (P less than 0.05). Thus, cimetidine has little or no influence on the absorption or disposition of oxazepam and lorazepam, two benzodiazepines biotransformed by glucuronide conjugation. However, cimetidine slows the elimination of flurazepam's metabolite, desalkylflurazepam, which is biotransformed by oxidation.

Pharmacokinetic volumes of distribution (Vd) are commonly calculated either by the steady-state method (Vdss) or the area method (Vdarea). Vdss is traditionally perceived as the least biased and most reliable indicator of the extent of distribution, but Vdss in fact has far greater practical and theoretical limitation than does Vdarea. After single doses or multiple discrete doses of a drug, Vdarea correctly relates plasma concentration to amount of drug in the body at all times after distribution equilibrium is attained. Vdss, on the other hand, is a correct proportionality constant only during continuous intravenous infusion or at a single instant in time after discrete dosing. Furthermore, calculated values of Vdss are strongly dependent on the precise configuration of the initial distributional phase of the plasma concentration curve, which may be difficult or impossible to delineate because of variance arising from methodologic artefacts or unexplained causes. Such variance can lead to large nonphysiologic within- and between-individual variability in Vdss. Vdarea, on the other hand, is relatively independent or artefactual changes in the initial distribution profile. Finally, experimental observations indicate that elimination depends physiologically on distribution in the absence of changes in clearance, not the reverse. The relation of distribution and elimination holds whether the steady-state method or the area method is used to calculate Vd. Thus, Vdarea is a more reliable and generally valid descriptor of the extent of drug distribution than is Vdss.

12 obese patients, pair-matched with 12 normal subjects, received a single 1 mg oral dose of alprazolam. Nine similar subject pairs received a single 0.5 mg oral dose of triazolam. Oral volume of distribution (Vd) was much greater in obese than control subjects for alprazolam (mean 114 vs 73L, p less than 0.001), but there was no difference between the 2 groups for triazolam (117 vs 116L). Apparent oral clearance (not corrected for body weight) of alprazolam was lower, although not significantly so, in obesity (66 vs 88 ml/min), but for triazolam it was much lower in the obese (340 vs 531 ml/min, p less than 0.005). Elimination half-life, which is dependent on both Vd and clearance, was prolonged in obesity for alprazolam (22 vs 11h, p less than 0.001) due to the increase in Vd, and also for triazolam (4.1 vs 2.6 h, p less than 0.025) because of the decreased clearance. Plasma protein binding was unchanged in obese compared with control subjects for both alprazolam and triazolam. During long term administration alprazolam should therefore take longer to reach steady-state concentrations in obese patients but the final levels achieved should be no different than for patients of normal bodyweight, provided dosage is adjusted for ideal rather than total bodyweight. In contrast, triazolam has impaired clearance in obesity. However, if given once-daily it still would not accumulate with long term dosing due to its short half-life relative to the interval between doses.

The effect of high concentrations of desmethyldiazepam (DMDZ), the major metabolite of diazepam (DZ), on parent drug kinetics was evaluated in six healthy young subjects who received a single intravenous dose (10 mg) of DZ on two occasions. The first DZ dose was given in the drug-free control condition and the second after the subject had ingested clorazepate (CZP), a precursor of DMDZ (15 mg daily for 7 days before DZ and then during the second DZ study). Maximum DMDZ concentration after the first DZ dose did not exceed 66 ng/ml, whereas mean DMDZ levels (derived from CZP) during the second DZ study were 481 +/- 61.5 ng/ml (SE) for all subjects. DZ kinetic parameters for all subjects during the first and second studies were: elimination half-life (t 1/2), 43.3 +/- 5.3 and 44.9 +/- 9.7 hr; total volume of distribution (Vd), 1.26 +/- 0.10 and 1.32 +/- 0.10 l/kg; unbound Vd, 97.4 +/- 9.9 and 94.9 +/- 9.9 l/kg; clearance, 0.364 +/- 0.048 and 0.394 +/- 0.055 ml/min/kg; and unbound clearance, 28.3 +/- 4.6 and 28.3 +/- 5.0 ml/min/kg. Percent unbound DZ was 1.40 +/- 0.25% when subject plasma was spiked with DZ alone and 1.47 +/- 0.21% when subjects' plasma was spiked with 500 ng/ml DMDZ in addition to DZ. Paired analysis of the two studies in each subject revealed no difference in t 1/2, Vd, unbound Vd, clearance, or DZ protein binding in the absence or presence of DMDZ. Formation and presence of the active metabolite DMDZ had no influence on kinetic behavior of parent DZ.

The effects of age, sex, and obesity on the kinetics of single intravenous (iv) and oral doses of midazolam were evaluated in healthy volunteers who received 2.5-5 mg of iv midazolam on one occasion and 5-10 mg orally on another. Kinetics were determined from multiple plasma midazolam concentrations measured during 24 h after dosage. Midazolam elimination half-life (t1/2) after iv dosage was significantly prolonged in elderly (aged 60-74 yr) versus young (24-33 yr) males (5.6 vs. 2.1 hours, P less than 0.01) and total clearance was significantly reduced (4.4 vs. 7.8 ml X min-1 X kg-1, P less than 0.01), leading to increased systemic availability of the oral dose (50% vs. 41%, P less than 0.05). However total volume of distribution calculated by the area method (Vd) (1.6 vs. 1.3 1/kg) and protein binding (3.5 vs. 3.4% unbound) did not differ between groups. Among women there were no significant differences between elderly (64-79 yr) and young (23-37 yr) volunteers in t1/2 (4.0 vs. 2.6 h), clearance (7.5 vs. 9.4 ml X min-1 X kg-1), Vd (2.1 vs. 2.0 1/kg), protein binding (3.7% vs. 3.7% unbound), or oral bioavailability (38% vs. 36%). In obese volunteers (mean weight 117 kg; 173% of ideal weight) versus control subjects of normal weight (66 kg, 95% of ideal weight) matched for age, sex, and smoking habits, midazolam Vd was increased significantly (311 vs. 114 1, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

A method with adequate sensitivity (to 0.50-0.75 mg/ml) for single-dose pharmacokinetic studies which utilizes gas-liquid chromatography with nitrogen-phosphorous detection for tricyclic antidepressants (imipramine, desipramine, amitriptyline, nortriptyline, and doxepin) is described. A basic (pH 13) extraction with acid back-wash and subsequent basic reextraction is used for plasma sample preparation. Standard curves, using clomipramine as the internal standard, are linear for concentrations from 1 to 200 ng/ml for all tricyclic antidepressants. Applicability of the method is demonstrated by a pharmacokinetic study in a normal volunteer who received 12.5 mg imipramine hydrochloride i.v.

Thirty-two healthy men and women, 23 to 78 yr old, received single 650-mg intravenous doses of acetaminophen and the drug's kinetics were determined from multiple plasma samples drawn over the next 8 to 12 hr. Acetaminophen elimination half-life averaged 2.7 hr (range, 1.9 to 4.3 hr) and was not related to age or sex. Volume of distribution (corrected for weight) was larger in men than in women (0.99 and 0.86 l/kg) and declined with age in both sexes. This probably reflects increased fat per kilogram body weight in women and in the elderly, together with incomplete distribution of this nonlipophilic drug into body fat. Acetaminophen clearance tended to decline with age in both sexes, but differences were of borderline significance. On the basis of kinetics data alone, adjustment of acetaminophen dosage for the elderly is generally not necessary.

The metabolic profile and human pharmacokinetics of alprazolam, a benzodiazepine of unique chemical structure, are discussed. Alprazolam's pharmacokinetics may be altered by age and sex, body weight, and concurrent treatment with cimetidine. The unique structure of alprazolam may be associated with a wider range of biologic activity than is seen with other benzodiazepines.

Elderly (65-73 years) and young (28-34) hypertensive patients received amlodipine by i.v. infusion (2.5, 5.0, or 10.0 mg). Patients were then started on oral amlodipine 2.5 mg daily for 2 weeks, at the end of which amlodipine disposition and effect were evaluated over one 24-h dose interval. Patients were treated subsequently with amlodipine in an escalating dose protocol (maximum 10.0 mg once daily) for 12 weeks to control blood pressure. After i.v. amlodipine, clearance tended to be decreased in elderly as compared with young patients with resulting prolongation in elimination half-life (64 +/- 20 vs. 48 +/- 8 h; mean +/- SD). Maximum decrease in systolic blood pressure (SBP) after i.v. doses tended to be greater in the elderly (-34 +/- 15 vs. -23 +/- 15 mm Hg) and maximum decrease in diastolic blood pressure (DBP) was similar in the two groups (-21 +/- 10 vs. -18 +/- 7 mm Hg). SBP was significantly decreased after 14 weeks' therapy in the elderly at doses ranging from 2.5 to 10.0 mg per day (171 +/- 17 to 149 +/- 22 mm Hg; p less than 0.01). DPB was decreased both at 2 and 14 weeks' therapy in the elderly (baseline 100 +/- 7, 2 weeks 93 +/- 5, 14 weeks 90 +/- 5 mm Hg; p less than 0.01 vs. baseline).(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil (0.15 mg/kg) was administered by 10-min intravenous infusion to 12 obese (127 +/- 8 kg) and 11 normal weight (74 +/- 4 kg) hypertensive patients. All subjects were of similar age and without clinical or laboratory evidence of cardiac or renal dysfunction. Verapamil plasma concentrations were determined and pharmacokinetic parameters derived. Electrocardiographic P-R interval, used as a measure of A-V nodal conduction, mean blood pressure, and heart rate were determined simultaneously with blood sampling for 24 h following the dose. Elimination half-life was prolonged in obese patients (10.1 +/- 1.8 vs. 3.6 +/- 0.4 h; p less than 0.005) due to a marked increase in volume of distribution at steady-state (713 +/- 99 vs. 301 +/- 33 L; p less than 0.005) with no change in total verapamil clearance [1,339 +/- 180 obese vs. 1,250 +/- 147 ml/min; not significant (NS)]. Verapamil plasma protein binding was similar between groups (percent unbound, 4.8 +/- 0.5 obese vs. 5.1 +/- 0.5%; NS). Using a sigmoid Emax pharmacodynamic model, Emax (maximal prolongation in P-R interval) was unchanged in obesity (53.7 +/- 12.5 obese vs. 45.9 +/- 12.0 ms; NS). However, EC50 (verapamil concentration required to achieve 50% of Emax prolongation in P-R interval) was greater in obese patients (45.9 +/- 6.7 vs. 22.6 +/- 2.0 ng/ml; p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetic parameters were derived from trimipramine and desmethyltrimipramine plasma concentrations after administration of intravenous (12.5 mg) and oral (50 mg) trimipramine in nine subjects. Elimination t1/2 after intravenous dosing was (mean +/- SE) 23 +/- 1.9 hr. Volume of distribution by the area method was 30.9 +/- 3.5 l/kg and total metabolic clearance was 15.9 +/- 1.5 ml/min/kg. Plasma protein binding of trimipramine, as determined by equilibrium dialysis, averaged 94.9%, with a range of 93.8% to 96.4%. Peak plasma level attained was 28.2 +/- 4.4 ng/ml at 3.1 +/- 0.6 hr after oral dosing. Absolute bioavailability was 41.4% +/- 4.4% (range of 17.8% to 62.7%). These data indicate that trimipramine has incomplete and variable systemic availability, that it is more highly protein bound than other tricyclic antidepressants, and, on the basis of its elimination t1/2, that it could be administered on a twice-daily basis without marked interdose fluctuations in plasma levels.

To assess the role of basal anesthesia in the negative inotropic properties of verapamil, the effect of thiopental (30 mg/kg followed by 3.5 mg.kg-1.min-1) on verapamil pharmacokinetics (200 micrograms/kg iv; n = 6) and its pharmacodynamics (3 and 6 micrograms.kg-1.min-1; n = 11) in chronically instrumented dogs was studied. In the presence of thiopental, verapamil pharmacokinetics remained essentially unchanged. In contrast, anesthesia altered verapamil hemodynamic properties. In the conscious animal verapamil infusions increased heart rate (14 +/- 3 and 27 +/- 4 beats/min, respectively), cardiac output (0.22 +/- 0.07 and 0.24 +/- 0.08, l/min, respectively) and PR interval (14 +/- 2 and 25 +/- 6 ms, respectively) and slightly decreased dP/dt (-315 +/- 114 and -419 +/- 106 mmHg/s, respectively). Systemic vascular resistance (SVR) decreased at the low dose (-2.7 +/- 0.7 mmHg.1.min-1), and stroke volume decreased at the high dose (-4.4 +/- 0.6 ml). Yet the presence of thiopental resulted in an accentuation of verapamil-induced tachycardia (27 +/- 7 and 31 +/- 6 beats/min, respectively), and a decrease in stroke volume (-5.3 +/- 2.0 and -6.3 +/- 2.1 ml, respectively). At 3 micrograms.kg-1.min-1 verapamil did not increase PR interval, cardiac output, or vasodilation. Finally, at 6 micrograms.kg-1.min-1 verapamil did not decrease dP/dt and increased renal blood flow (21.8 +/- 6.4 ml/min). These data provide evidence that the negative inotropic properties of verapamil are more pronounced in the presence of thiopental. However, the role of basal anesthesia appears to be limited.

To evaluate the effect of diltiazem on antipyrine disposition and metabolism, 10 healthy subjects received 1.2 gm antipyrine on two occasions, once while taking no other medications and once during long-term oral diltiazem, 120 mg three times daily. Antipyrine oral clearance was markedly reduced from (mean +/- SEM) 41.7 +/- 4.1 to 29.9 +/- 2.8 ml/min (P less than 0.01) during diltiazem treatment, resulting in prolongation of antipyrine elimination t1/2 from 12.2 +/- 1.0 to 16.7 +/- 1.3 hours (P less than 0.01), with no change in apparent volume of distribution (42.1 +/- 4.0 vs. 41.3 +/- 3.1 L; not significant). Measurement of urinary antipyrine and metabolites excreted in the urine during 24 hours after the antipyrine dose (percent of total 24-hour excretion) showed increased antipyrine (4.4% +/- 1.0% vs. 7.8% +/- 1.6%; P less than 0.01) during diltiazem treatment with no significant change in proportion of 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine excretion between trials. Chronic oral diltiazem in therapeutic doses markedly impairs antipyrine oxidation. Diltiazem may therefore impair the clearance of other coadministered drugs that undergo hepatic oxidation.

The widely used plasticizer and rodent carcinogen di-(2-ethylhexyl) phthalate (DEHP) was examined for activity in the C3H 10T 1 2 murine fibroblast cell transformation system. Treatment with DEHP or its metabolite, mono-(2-ethylhexyl) phthalate, did not produce oncogenic transformation, initiate the process of transformation in cultures treated with a tumour promoter or promote the process of transformation in cultures pretreated with a chemical carcinogen. These findings are consistent with the suggestion that the carcinogenicity of DEHP is mediated by an indirect mechanism and not by covalent interaction of DEHP with DNA.

The mutagenicity of technical grade 2,4-dinitrotoluene (DNT), a mixture composed predominantly of 2,4-DNT (76.5%) and 2,6-DNT (18.8%) but containing 3,4-, 2,3-, 2,5- and 3,5-DNT, and the 6 isomers of DNT has been determined in 3 assays with Salmonella typhimurium. The mixture and the individual isomers of DNT were found to be mutagenic in the Ames' Salmonella/microsome test, particularly in strains responding to frame-shift mutagens; 3,5-DNT was found to be the most effective isomer in inducing reversion to histidine prototrophy in S. typhimurium strains TA98 and TA1538. Similar results were obtained with a quantitative reversion assay using strain TA98; 3,5-DNT was the most mutagenic of the compounds examined, particularly in the absence of post-mitochondrial supernants of rat-liver homogenates. While all isomers and the mixture of DNTs increased the 8-azaguanine-resistant fraction of S. typhimurium TM677 to some degree, the greater mutagenicity of 3,5-DNT compared to other isomers was not evident in the forward mutational assay.

The effect of ketoconazole on the kinetics of antipyrine was investigated. The antipyrine Vd showed an overall difference among the 4 trials, but the magnitude of the differences was small. Antipyrine half-life was slightly but not significantly shortened and the antipyrine clearance was essentially identical in the whole study. The data are commented and interpreted.

1 Twelve young (ages 30-39 years) and twelve elderly (ages 65-83 years) hypertensives were administered diltiazem twice daily for 2 weeks at doses up to 240 mg day-1. 2 Plasma was analysed for diltiazem, N-monodesmethyldiltiazem, and desacetyldiltiazem concentrations after a single 10 min intravenous infusion of 21.8 mg diltiazem HCl on day 1 and after the morning oral dose of 120 mg diltiazem base on day 14. 3 N-monodesmethyldiltiazem accumulated to higher plasma concentrations than desacetyldiltiazem at steady state on day 14 in both age groups. 4 Prolongation of plasma diltiazem half-life occurred after 2 weeks of oral diltiazem therapy in both age groups. 5 There were no significant differences between the young and elderly with regard to half-life, area under the curve, and the peak and trough plasma concentrations of diltiazem, N-monodesmethyldiltiazem, and desacetyldiltiazem; systemic clearance and volume of distribution of diltiazem were also similar in both groups.

Potential interactions of ranitidine with antipyrine, diazepam, and lorazepam were evaluated. Ten healthy male subjects were injected intravenously with antipyrine (1.2 gm), diazepam (10 mg), or lorazepam (2 mg) on two randomly assigned occasions, once in the otherwise drug-free state and once while concurrently taking a therapeutic ranitidine dose of 150 mg every 12 hr. Kinetic analysis for antipyrine showed no change in elimination t1/2 between trials (mean, 11.6 and 11.5 hr) with no change in volume of distribution (Vd) or total clearance (0.77 and 0.75 ml/min/kg). Diazepam analysis also showed unchanged t1/2 (32.3 and 28.9 hr) with no change in Vd or total clearance (0.42 and 0.39 ml/min/kg). Lorazepam as well had unchanged t1/2 (11.7 and 11.3 hr), Vd, and total clearance (1.52 and 1.65 ml/min/kg). Therefore ranitidine, unlike cimetidine, has no effect on either human hepatic drug oxidation, as measured by antipyrine and diazepam clearance, or human drug conjugation, as measured by lorazepam clearance.

Ten women on long-term, low-dose estrogen oral contraceptive steroids (OCS) and eight age-matched drug-free female controls received an intravenous infusion of 12.5 mg imipramine. Eleven (six OCS users and five controls) also took a 50-mg oral dose of imipramine on another occasion. After intravenous injection, volume of distribution was much the same in the OCS and control groups and clearance was of the same order (899 and 975 ml/min). Elimination t1/2 was prolonged in OCS users after intravenous doses (17.8 vs 25.5 hr) but did not change after oral doses (18.4 vs 19.1 hr). Imipramine plasma protein binding was of the same order in both groups. Absolute bioavailability increased in OCS users (from 27.1% vs 44.1%), which resulted in a trend toward decreased apparent oral clearance (from 4649 vs 2322 ml/min). Women who used OCS regularly show little change in imipramine kinetics after intravenous dosing. After oral dosing absolute systemic bioavailability increased, resulting in decreased apparent oral clearance in the absence of any change in oral elimination t1/2. Imipramine (with high first-pass hepatic extraction) is nonrestrictively cleared, with drug elimination predominantly a function of hepatic blood flow. These data are consistent with OCS inhibition of hepatic imipramine oxidation with no alteration in hepatic blood flow resulting from chronic OCS use.

Eleven obese subjects (weight 114 +/- 11 kg, mean +/- SE) and 11 age-matched subjects with normal body weight (61 +/- 3 kg) were given 600 mg of ibuprofen orally after an overnight fast. Peak ibuprofen concentration was significantly decreased in obese subjects (P less than 0.02), although the time from administration to peak concentration was not different. Ibuprofen volume of distribution was increased in obese subjects, and this increased distribution correlated positively with body weight (r = 0.82; P less than 0.001). Volume of distribution corrected for body weight was decreased in obese subjects, and this decrease correlated negatively with body weight. Ibuprofen clearance was also increased in obese subjects; the increase correlated positively with body weight (r = 0.81; P less than 0.001). Since the independent variables, volume of distribution and clearance, were increased in parallel in the obese subjects, the dependent variable, elimination half-life, was unchanged. Using mean values of distribution calculated from the 2 groups, ibuprofen distribution into body weight in excess of ideal body weight was found to be approximately 0.44 times as extensive as the distribution into ideal body weight. Furthermore, ibuprofen clearance increased in parallel with the volume of distribution and total body weight. Clinically, these data indicate that in obese patients, the ibuprofen dose may be increased without changing the dose interval, in order to achieve necessary plasma concentrations.

Pharmacodynamics and pharmacokinetics of labetalol, a combined alpha- and beta-adrenoceptor antagonist drug, were studied in elderly and young hypertensive patients. After receiving intravenous labetalol, elderly patients had a greater maximal mean decrease in systolic blood pressure (BP) (39 +/- 8 vs 25 +/- 13 mm Hg, p less than 0.02); however, maximal decrease in diastolic BP was similar in elderly (18 +/- 10 mm Hg) and young (17 +/- 6 mm Hg) patients. After receiving oral labetalol, elderly patients had a greater maximal decrease in standing systolic BP (41 +/- 16 vs 16 +/- 14 mm Hg, p less than 0.001) and similar decreases in standing diastolic BP (21 +/- 7 vs 17 +/- 9 mm Hg). Sitting maximal BP decreases after oral labetalol treatment were similar in elderly and young patients (12 +/- 16 vs 17 +/- 7 mm Hg systolic and 24 +/- 6 vs 12 +/- 7 diastolic). The decrease in heart rate was greater in young patients after intravenous labetalol administration. To evaluate labetalol pharmacodynamics, a linear model was used. Slope of labetalol concentration vs systolic BP for elderly vs young patients was 0.928 +/- 1.05 vs 0.326 +/- 0.490 ng/ml X mm Hg-1 (difference not significant). The slope of labetalol concentration vs heart rate for elderly vs young patients was 0.176 +/- 0.063 vs 0.406 +/- 0.303 ng/ml X beats/min-1 (p less than 0.05), with 2 elderly patients showing no decrease in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty-eight healthy volunteers (age range, 22-78 years) received 650 mg of acetaminophen (AAP) on three separate occasions. The modes of administration were 1) intravenous, 5-minute infusion; 2) oral, with two 325-mg tablets; and 3) oral, with 650 mg as an elixir preparation. Plasma levels of AAP were determined in blood samples drawn up to 12 hours after the dose. The mean (+/- sd) kinetic variables for absorption of AAP from tablets in young and elderly were peak plasma concentration, 11.8 (+/- 4.2) vs 10.9 (+/- 4.1) micrograms/ml; peak time, 0.79 (+/- .54) vs 0.69 (+/- .40) hours after the dose; absorption half-life, 12.6 (+/- 9.8) vs. 8.2 (+/- 5.3) minutes; and absolute systemic availability, 79 (+/- 9) vs 72 (+/- 11) per cent. For AAP elixir, the corresponding values were 12.6 (+/- 5.4) vs 13.7 (+/- 6.0) micrograms/ml; 0.52 (+/- .24) vs 0.54 (+/- .51) hours; 8.6 (+/- 6.2) vs 6.1 (+/- 6.6) minutes; and 87 (+/- 9) vs 80 (+/- 9) per cent. Absolute bioavailability of both oral dosage forms was significantly less then 100 per cent in all groups. Elderly subjects tended to show lower availability of both oral preparations, but the difference was of borderline significance (P less than .50). Age did not influence any other measures of absorption. Since the absorption rate of acetaminophen may be indicative of the gastric emptying rate, age does not appear to alter this rate-limiting step in drug absorption.

Thirty-three healthy male and female volunteers aged 21 to 87 years received a single 0.5 mg oral dose of triazolam. Plasma triazolam concentrations were measured in multiple samples drawn during 24 h after the dose. Mean triazolam elimination half-life was not significantly different between young and elderly men (3.0 vs 4.6 h), nor between young and elderly women (2.7 vs 3.2 h). However, apparent oral clearance of triazolam was significantly reduced in elderly as compared to young groups of both sexes, leading to higher peak plasma concentrations and increased total area under the curve. Values of half-life and clearance of antipyrine, a low-extraction hepatically oxidized compound, were poorly correlated with those of triazolam (r = 0.34 and 0.44, respectively), suggesting different mechanisms controlling age-related changes in clearance of these two hepatically oxidized drugs.

During acute and chronic administrations of lithium, 25 patients were studied to determine the effect of other psychotropic drugs on the plasma-saliva lithium concentration correlations. Changes, even discontinuation, in either tricyclic antidepressants or neuroleptics did not affect the plasma-saliva ratio which had an overall correlation coefficient of r = 0.79 (p less than 0.01). The relationship using linear regression analysis was described by the equation, y = 2.27x--0.45. Individual patients' plasma-salivary relations were described by this equation in 87% of cases. The study extends the usefulness of these determinations to include patients on lithium and neuroleptics or tricyclic antidepressants.

Fourteen obese men (mean weight 124 +/- 8 kg (+/- standard error of the mean), percent ideal body weight (IBW) 169 +/- 10%), 11 obese women (96 +/- 6 kg; 174 +/- 11% IBW), 19 control men (69 +/- 1 kg; 93 +/- 2% IBW), and 12 control women (59 +/- 2 kg; 102 +/- 3% IBW), all of similar age and without clinical or laboratory evidence of cardiac or renal dysfunction, received a single 25-mg intravenous dose of lidocaine. Elimination half-life was markedly prolonged in obese compared with control men (2.69 +/- 0.2 vs 1.62 +/- 0.06 hour, p less than 0.001) and in obese compared with control women (2.95 +/- 0.1 vs 2.08 +/- 0.06 hour, p less than 0.01). This was not the result of a change in clearance (men, obese vs control: 1,427 +/- 117 vs 1,346 +/- 86 ml/min, difference not significant, [NS]; women: 1,089 +/- 83 vs 1,162 +/- 84 ml/min, NS), but rather of an increased absolute volume of distribution (Vd) in obese men (325 +/- 29 vs 186 +/- 12 liters, p less than 0.001) and obese women (264 +/- 20 vs 209 +/- 15 liters, p less than 0.025). Vd corrected for total body weight was unchanged in obesity for both men (2.67 +/- 0.22 vs 2.71 +/- 0.18 1/kg, NS) and women (2.88 +/- 0.31 vs 3.57 +/- 0.25, NS), suggesting that lidocaine Vd increases in parallel with body weight in both sexes. Because lidocaine clearance is determined mainly by hepatic blood flow, these findings suggest that extremes of body weight do not change hepatic blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma binding of imipramine and lidocaine, two drugs that bind predominantly to alpha-1 acid glycoprotein (AAG), and of diazepam and phenytoin, albumin-bound drugs, were studied in fresh human plasma. Binding was determined by equilibrium dialysis with 0.1 M pH 7.4 phosphate buffer at 37 degrees C. AAG was determined by immunodiffusion. Lidocaine free fraction (FF) (30-35%) was time-dependent, reaching equilibrium by five hours. However, dialysis time exceeding 8 hours greatly increased lidocaine FF (60%) accompanied by a decrease in AAG concentration. Lidocaine binding and AAG-concentration were not affected by plasma freezing, and were independent of lidocaine concentrations from 0.5-10 micrograms/ml. Imipramine behaved comparably, with FF increasing from 15% at 5 hours of dialysis to 30% at 24 h, concurrent with a drop in AAG concentration. Imipramine binding and AAG concentration were also independent of plasma freezing and drug concentration from 0.25 to 10.0 micrograms/ml. Binding of diazepam (FF = 1.2%) and phenytoin (FF = 17%) were stable at 24 hours, not affected by sample freezing or drug concentration, and were independent of AAG concentration. Therefore, changes in AAG concentration alter plasma protein binding of AAG-bound drugs lidocaine and imipramine. Extended dialysis results in decreased concentrations of immunoreactive AAG and increased FF. In contrast, the binding of albumin-bound drugs diazepam and phenytoin are not affected by these variables.

Current knowledge of the effects of aging on drug disposition is reviewed. Although definitive studies are not always available, based on present evidence it appears that: 1) drug absorption is not impaired in the elderly; 2) drug distribution in the elderly may be altered by significant changes in the lipid/lean body mass ratio; 3) Phase I (non-synthetic) biotransformation reactions of the liver appear to be much more profoundly affected by aging than are Phase II (synthetic) reactions; 4) age-related effects of biotransformation can be different even for compounds that are very similar and undergo the same types of reactions. Important parameters of drug metabolism are also discussed, such as the need to use total clearance, rather than half-life, in assessing 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 age-related 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.

1 Eight patients with end-stage renal insufficiency on maintenance haemodialysis, and seven patients with newly diagnosed hyperthyroidism, received a single intravenous dose of diazepam, followed by blood sampling over the next 7 days. Fifteen healthy volunteer controls, matched with patients for age and sex, were similarly studied. 2 Diazepam half-life in renal failure patients (mean 37 h) was greatly reduced compared to controls (mean 92 h, P less than 0.05) and clearance of total (free plus bound) diazepam correspondingly increased (0.94 v 0.34 ml min-1 kg-1, P less than 0.01). 3 However, differences were largely related to disease-related changes in drug binding and distribution. Mean unbound fraction of diazepam in plasma of renal patients (7.0%) was greatly increased over controls (1.4%, P less than 0.01) and Vd of unbound diazepam greatly reduced (57 v 157 l/kg, P less than 0.01). 4 Clearance of pharmacologically active unbound diazepam (intrinsic clearance) was not significantly different between renal patients and controls (23 vs 30 ml min-1 kg-1). 5 None of the kinetic variables for total or unbound diazepam in thyrotoxic patients differed significantly from those in controls matched for age and sex. 6 End-stage renal failure (or its associated drug therapy) alters diazepam protein binding and distribution, but does not significantly change clearance of unbound drug. Thyrotoxicosis does not influence diazepam kinetics.

Sixteen young (21-40 years) and nine elderly (65-78 years) volunteers received single intravenous doses of antipyrine on two occasions: once in the control state, and again while receiving therapeutic doses of cimetidine (300 mg every six hours). In the control state, antipyrine half-life was longer in elderly than in young subjects (16.4 vs 11.0 hours), and metabolic clearance lower (0.48 vs 0.72 ml/min/kg). However, coadministration of cimetidine prolonged antipyrine half-life to a similar extent in elderly and in young groups (150 and 153 per cent of control) and reduced metabolic clearance to a similar extent in both (79 vs 69 per cent of control) groups. Three young and six elderly volunteers received a single 15 mg oral dose of clorazepate, a precursor of desmethyldiazepam, with and without cimetidine. As in the case of antipyrine, cimetidine prolonged desmethyldiazepam half-life similarly in young and elderly groups (175 vs 164 per cent of control) and similarly reduced metabolic clearance (51 vs 65 per cent of control). The elderly population may already have an impaired capacity to oxidize drugs. This capacity is further impaired by coadministration of cimetidine.

Diminished intercellular communication has been associated with heightened sensitivity of cultured cells to morphological transformation and enhancement of transformation by tumor promoters. Microinjection of Lucifer yellow dye was employed to evaluate intercellular communication between transformable C3H/10T1/2 murine fibroblasts under a variety of culture conditions. Intercellular communication assayed by dye transfer from injected cells to surrounding cells in contact occurred in logarithmically growing cultures, declined to very low levels as confluence was attained, and then resumed upon the formation of mature confluent monolayers. Dye-transfer networks of 50 or more cells resulted from injection of single monolayer cells. Freeze-fracture electron microscopy confirmed the presence of gap junction structures in confluent cultures. Treatment with the initiating agent N-methyl-N'-nitro-N-nitrosoguanidine and/or the tumor promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin did not inhibit intercellular communication between C3H/10T1/2 cells during 6-week transformation experiments. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate produced a transient inhibition of dye-coupling upon first introduction to cultures and prolonged the period of diminished dye-coupling at the attainment of confluence, but did not inhibit subsequent interactions between monolayer cells. A simple relationship thus could not be established between levels of dye-coupling within monolayers and focus formation events. Curiously, although the cells of foci in early phases of development did not exhibit dye-transfer capacity, dye-coupling was observed in mass cultures of most transformed cell lines cloned from foci. Co-cultivation of communication-competent transformed cells with nontransformed cells to produce reconstructed foci generally resulted in a cessation of dye-transfer by transformed cells. An often reversible loss of communication competence thus accompanies the growth of transformed C3H/10T1/2 cells as foci and may constitute an adaptive response which facilitates focus growth in the presence of intercellular communication between monolayer cells.

A sensitive (to 3 ng/ml) and specific method for analysis of the benzodiazepine antagonist Ro 15-1788 is described. The method utilizes gas-liquid chromatography with nitrogen-phosphorus detection. A neutral pH ethyl acetate extraction of 0.1-3.0 ml plasma is used for sample preparation. Standard curves using methylclonazepam as the internal standard are linear for plasma concentrations up to 200 ng/ml. Applicability of the method is demonstrated by a pharmacokinetic study in a normal volunteer who received 10 mg Ro 15-1788 intravenously.

Reduced drug metabolism, both renal and hepatic, occurs with aging. Algorithms for dose adjustments of renally excreted drugs are available, but dose adjustments must be empiric for drugs which undergo hepatic metabolism. Decreased drug clearance in combination with potentially increased sensitivity to drugs in the elderly means that, as a general rule, drug dosages should be reduced as the age of the patient increases. The frequent need for multi-drug therapy may also lead to adverse effects in the elderly compared with younger cardiac patients. Managing the geriatric patient requires careful drug monitoring and a heightened awareness of the potential for adverse drug effects.

Rapid and sensitive methods are described for determining lorazepam and for determining chlordiazepoxide and its metabolites in brain tissue of the rat. Lorazepam was determined by means of solvent extraction and electron-capture gas-liquid chromatography and concentrations as low as 5 ng/g tissue could be measured. High-performance liquid chromatography with UV detection was used to determine chlordiazepoxide and its metabolites and was sensitive to 0.1 micrograms/g tissue. The methods were used to investigate the brain and plasma pharmacokinetics of these compounds in animals that had been chronically treated with lorazepam or chlordiazepoxide. In both experiments brain and plasma levels of all compounds assayed were found to correlate highly.