Automated gas chromatographic determination of plasma alprazolam concentrations.
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Alprazolam↗
Biomedical subjects
M Divoll
Publications and source records attributed to M Divoll.
Differential effect of cimetidine on drug oxidation (antipyrine and diazepam) vs. conjugation (acetaminophen and lorazepam): prevention of acetaminophen toxicity by cimetidine.
Fourteen healthy volunteers received a single i.v. dose of antipyrine (1.2 g) on two occasions, once before and once during cimetidine treatment (300 mg every 6 hr). In a similar manner, 8 subjects received diazepam (10 mg), 11 subjects received acetaminophen (650 mg) and 8 subjects received lorazepam (2 mg), all by the i.v. route, once before and once during cimetidine coadministration. Pharmacokinetic analysis indicated increased antipyrine elimination T1/2 during cimetidine treatment (16.7 vs. 10.9 hr; P less than .001) on the basis of decreased total metabolic clearance (0.46 vs. 0.72 ml/min/kg; P less than .001). Likewise, diazepam T1/2 was increased (58 vs. 39 hr; P less than .01) during cimetidine treatment due to decreased total metabolic clearance (0.42 vs. 0.30 ml/min/kg; P less than .01). In contrast, cimetidine did not alter T1/2 or the clearance of lorazepam (T1/2, 16.8 vs. 15.3 hr; clearance, 1.03 vs 1.07 ml/min/kg) or acetaminophen (T1/2, 2.66 vs. 2.60 hr; clearance, 4.8 vs. 4.5 ml/min/kg), both drugs which undergo conjugative biotransformation. In an animal model used to assess the effect of cimetidine on acetaminophen toxicity, the LD50 of acetaminophen alone in Charles River CD-1 mice was 480 mg/kg (95% confidence interval: 436-528 mg/kg). With simultaneous 75 mg/kg of cimetidine treatment, the LD50 for acetaminophen was significantly increased (P less than .05) to 1020 mg/kg (95% confidence interval: 962-1081 mg/kg). Thus, cimetidine slows the metabolic clearance of antipyrine and diazepam, drugs biotransformed by hepatic oxidation, but does not alter the kinetics of acetaminophen or lorazepam, both metabolized by conjugation. Cimetidine may decrease the toxicity of high-dose acetaminophen by preventing formation of the hepatotoxic oxidative metabolites, although having no effect on conjugation of acetaminophen which yields nontoxic metabolites that are subsequently cleared from the body.
Acetaminophen↗
Kinetics of low-dose intravenous antipyrine: use of liquid chromatography.
Rapid and sensitive quantitation of antipyrine in plasma is achieved by high-pressure liquid chromatography. Antipyrine and phenacetin, the internal standard, are readily extracted from alkalinized plasma into ethyl acetate. After evaporation of the organic solvent, the redissolved residue is chromatographed using a reverse-phase C-18 column. The sensitivity limit is approximately 0.25 micrograms antipyrine per ml plasma, with a coefficient of variation for identical samples not exceeding 3%. Using the automated sampling system, one person can analyze up to 100 samples per day. The method is reliable and sensitive enough to allow human pharmacokinetic studies of antipyrine using doses considerably less than utilized in previous studies. The disposition kinetics of a single i.v. dose of antipyrine in four human volunteers were essentially identical over a 5-fold range of doses.
Adult↗
Absolute bioavailability of oral and intramuscular diazepam: effects of age and sex.
Twenty-two healthy volunteers aged 20-78 years received single 5-mg doses of diazepam by intravenous injection, by mouth in the fasting state, and by a deltoid intramuscular injection. The kinetic profile of diazepam by each route was determined from multiple plasma diazepam concentrations measured 7-14 days after each dose. After intravenous injection, diazepam volume of distribution (Vd) was larger in women than in men, but increased with age regardless of sex. Elimination half-life was longer in elderly than in young men (101 v 32 h, P less than 0.025), partly due to the increased Vd as well as to a significant reduction in total metabolic clearance (0.24 v 0.46 ml/min/kg, P less than 0.05). However, the prolonged half-life in elderly as opposed to young women (99 v 44 h; P less than .01) was due mainly to increased Vd because clearance was not significantly changed (0.29 v 0.35 ml/min/kg). In all subjects, oral diazepam was rapidly absorbed; peak plasma levels were reached an average of 0.9 h after dosage. Absolute bioavailability averaged 94%, indicating essentially complete absorption. Neither age nor sex significantly influenced oral absorption. In all male subjects, and in 8 of 12 women, absorption of diazepam after deltoid intramuscular injection was rapid and essentially complete. However, in three young and one elderly women, absorption was slower and apparently incomplete. Age as such did not significantly influence absorption of intramuscular diazepam.
Administration, Oral↗
Impairment of diazepam metabolism by low-dose estrogen-containing oral-contraceptive steroids.
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Adult↗
Clobazam kinetics: intrasubject variability and effect of food on adsorption.
The kinetics of single 20-mg oral doses of clobazam was determined on two occasions in 12 healthy male volunteers. Clobazam was given in the fasting state on one occasion and following a standard breakfast on another. Compared with the fasting state, administration of clobazam with food reduced mean peak plasma concentrations (465 vs. 333 ng/ml, P less than 0.01), and prolonged the time to reach peak concentration (1.7 vs. 2.5 hours after dosage, P less than 0.1). Total area under the curve nor the extent of formation of desmethylclobazam, the major metabolite. Clobazam AUC and elimination half-life each were highly correlated within subjects between the two trials (r = 0.97 and 0.95, respectively). Thus, administration of clobazam with food slows the rate of clobazam absorption but does not alter the completeness of absorption. The rate of drug elimination is highly replicable upon repeated administration clobazam to the same individual.
Adult↗
Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam.
Ten healthy volunteers received single 2-mg doses of lorazepam on five occasions in random sequence. Modes of administration were: A, intravenous injection; B, deltoid intramuscular injection; C, oral tablets in the fasting state; D, sublingual dosage of oral tablets in the fasting state; and E, sublingual dosage of specially formulated tablets in the fasting state. Kinetic variables were determined from multiple plasma lorazepam concentrations measured during 48 hr postdose. After intravenous lorazepam, mean (+/- SE) values were: elimination half-life (t 1/2 beta), 12.9 (+/- 0.8) hr; volume of distribution, 1.3 (+/- 0.07) liters/kg; total clearance, 1.21 (+/- 0.1) ml/min/kg. Absorption of intramuscular lorazepam was rapid. Peak plasma levels were reached at 1.15 hr after dosage, with absorption half-life averaging 14.2 (+/- 4.7) min. Absorption or oral and sublingual lorazepam tended to be less rapid than intramuscular injection, although differences were not significant. Times of peak concentration were 2.37, 2.35, and 2.25 hr postdose for trials C,D, and E, respectively; values of absorption half-life were 32.5, 28.5, and 28.7 min. Absolute systemic availability for trials B, C, D, and E averaged 95.9, 99.8, 94.1, and 98.2%, respectively; none of these differed significantly from 100%. Values of t1/2 beta were highly replicable within individuals regardless of the administration route. Thus, sublingual lorazepam is completely absorbed and is a suitable administration route in clinical practice.
Administration, Oral↗
Prolongation of drug half-life due to obesity: studies of desmethyldiazepam (clorazepate).
Desmethyldiazepam pharmacokinetics were determined after oral administration of its precursor, clorazepate, to 12 obese subjects (mean weight: 105.4 kg; mean percent ideal body weight: 170%) who were matched for age, sex, and smoking habits with 12 normal controls (66.5 kg; percent ideal body weight: 103.3%). After an overnight fast, a single 15-mg clorazepate capsule, equivalent to 10.3 mg of desmethyldiazepam, was administered. Multiple plasma samples drawn 10-42 days postdose were analyzed for desmethyldiazepam by electron-capture GLC. Obese subjects compared to controls had a prolonged desmethyldiazepam elimination half-life (t1/2) (154.1 hr versus 57.1 hr; p less than 0.005). Assuming quantitative conversion of clorazepate to desmethyldiazepam and 100% systemic availability, volume of distribution (Vd) was greatly increased in the obese (158.8 liters versus 63.3 liters; p less than 0.001). The value of Vd remained greater even after correction for body weight (1.52 liter/kg versus 0.94 liter/kg; p less than 0.005). However, clearance of desmethyldiazepam was not different between groups (13.2 ml/min in obese versus 13.4 ml/min in controls). The percent ideal body weight was highly correlated with Vd (r = 0.82), as was total body weight (r = 0.86). The value of t1/2 was correlated highly with Vd (r = 0.89) but only weakly with clearance (r = -0.38). Therefore, the large increase in the desmethyldiazepam t1/2 value seen in obese subjects is predominantly due to the disproportionate distribution of this lipid-soluble drug into body fat as opposed to lean tissue. The contribution of clearance to desmethyldiazepam t1/2 was of much less importance than was Vd in this obese study population.
Adult↗
Obesity, sex, and acetaminophen disposition.
Twenty-one obese (14 women; 7 men) and 21 normal (11 women; 10 men) drug-free and age-matched subjects were given single 650-mg IV doses of acetaminophen. Mean total body weights (TBW) for the groups were as follows: obese men, 134.9 kg; control men 70.6 kg; obese women, 87.9 kg; and control women, 55.0 kg; ideal body weight (IBW) was similar for all of the groups. Acetaminophen elimination half-life (t1/2 beta) did not differ among groups. Absolute volume of distribution (Vd) was greater in obese than in control men (109 and 77 l, P less than 0.05) and greater in control men than in control women (77 and 52 l, P less than 0.05), but Vd corrected for TBW was smaller in obese than in control men (0.81 and 1.09 l/kg TBW, P less than 0.05) and smaller in obese than control women (0.71 and 0.95 l/kg TBW, P less than 0.05). Absolute metabolic clearance was greater in obese than in control men (484 and 323 ml/min, P less than 0.05), in obese than in control women (312 and 227 ml/min, P less than 0.05), and in control men than women (323 and 227 ml/min, P less than 0.05). After correction for TBW, however, clearance between control and obese subjects of the same sex did not differ. Acetaminophen Vd is increased in obesity and in men relative to women, but the drug's distribution into body weight exceeding IBW is less extensive than that into IBW. For men the distribution ratio is 0.44 and for women, 0.31. Acetaminophen clearance increases with body weight and therefore is much greater in obese patients and in men.
Acetaminophen↗
Acetaminophen kinetics in the elderly.
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.
Acetaminophen↗
Benzodiazepine hypnotics: kinetic and therapeutic options.
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Anti-Anxiety Agents↗
Physiologic changes in old age: relation to altered drug disposition.
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.
Aged↗
Cimetidine impairs clearance of antipyrine and desmethyldiazepam in the elderly.
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.
Adult↗
Age does not alter acetaminophen absorption.
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.
Acetaminophen↗
Effect of age and sex on lorazepam protein binding.
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Adult↗
Liquid chromatographic determination of chlordiazepoxide and metabolites in plasma.
Sensitive quantitation of chlordiazepoxide and its two principal metabolites, desmethylchlordiazepoxide and demoxepam, in human plasma is achieved by high-pressure liquid chromatography. All three compounds and the internal standard, chlorodesmethyldiazepam, are directly extracted from plasma into benzene:isoamyl alcohol (98.5 : 1.5) at physiologic pH with no sample preparation. After evaporation of the organic solvent, the redissolved residue is chromatographed using a C-18 reverse-phase column. Sensitivity limits are 0.05 microgram of either compound/ml of plasma, with coefficients of variation of less than 8%. The method is applicable to single-dose pharmacokinetic studies of chlordiazepoxide or to monitoring of plasma concentrations during long-term therapy.
Aged↗
Pharmacokinetics of benzodiazepine hypnotics.
Three benzodiazepine derivatives are currently indicated specifically for the treatment of insomnia in the United States. Flurazepam is biotransformed to at least two rapidly appearing and rapidly eliminated intermediate metabolites which probably contribute to sleep induction. The final metabolite, desalkylflurazepam, appears slowly, but has a long half-life ranging from 40 to 150 h. This metabolite accumulates extensively during multiple dosage. Temazepam is a slowly absorbed drug and has an intermediate half-life in the range of 10-20 h. Triazolam has an intermediate absorption rate, but is rapidly eliminated (half-life 1.5-5 h) making it essentially non-accumulating. Understanding of the pharmacokinetics of benzodiazepine hypnotics can contribute to understanding of their clinical properties.
Anti-Anxiety Agents↗
Increased metabolic clearance of acetaminophen with oral contraceptive use.
The effect of chronic low-dose oral contraceptive steroid use on the pharmacokinetics of intravenous acetaminophen was determined. Eight women using low-dose (under 50 micrograms) estrogen oral contraceptive steroid for more than 3 months were matched for age and weight (mean age, 25.9 years; mean weight, 58.3 kg) with 8 female controls not using the steroid (mean age, 26.0 years; mean weight, 55.5 kg). No subject was taking other drugs. Oral contraceptive steroid subjects had a lower elimination half-life of acetaminophen (2.12 hours) than controls (2.71 hours) (P less than .005). Volume of distribution was similar for both groups (oral contraceptive group, 1.04 liters/kg; controls, 0.96 liters/kg; NS). Total metabolic clearance was significantly higher in oral contraceptive subjects (5.81 ml/min/kg, versus 4.12 ml/min/kg for controls; P less than .02). As volume of distribution and body weight are similar for both groups, the decrease in acetaminophen elimination half-life among contraceptive steroid users is the result of increased total metabolic clearance. Thus, low-dose estrogen oral contraceptive steroid may stimulate the metabolism of a conjugatively metabolized drug such as acetaminophen, in contrast to contraceptive steroid impairment of the clearance of some oxidatively metabolized drugs, with antipyrine being the prototype.
Acetaminophen↗