摘要:

To evaluate the influence of enflurane anesthesia on the hepatic drug‐metabolizing capacity, antipyrine half‐life was measured in 18 surgical patients before surgery and on days 4 and 8 after anesthesia. The effect of repeated administration of antipyrine on the rate of antipyrine metabolism was also evaluated in nine control subjects. Simultaneous measurement of plasma fluoride concentration allowed enflurane metabolism to be quantitated. Regardless of duration, enflurane anesthesia did not increase the rate of antipyrine metabolism as indicated by the absence of significant change in antipyrine half‐life and clearance. Repeated doses of antipyrine to nine normal subjects did not influence the rate of antipyrine metabolism. Preanesthesia elimination rate of antipyrine did not indicate individual capacity to metabolize enflurane. Mean peak fluoride level (10.7 ± 4.8 µM) was reached 3 hr after anesthesia and did not appear to correlate with duration of exposure to enflurane.Clinical Pharmacology and Therapeutics(1981)29,61–64; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1981.11

年代:1981

数据来源: WILEY

摘要:

In healthy, nonmedicated male subjects, patterns of eating and fasting determined diurnal variations in aminopyrine disposition. Under dietary conditions used in our laboratory to study temporal variation in the disposition of aminopyrine (a 12‐hr fast preceding 8A.M.dose and a 5P.M.meal before 8P.M.drug dosing) there was a mean diurnal variation of 33% in saliva aminopyrine half‐life (t½) and of 46% in apparent volume of distribution (aVd) with shorter t½ and lower aVd at 8A.M.Mean metabolic clearance rate (Cl) was unchanged. Fasting for 32 and 44 hr before aminopyrine at 8A.M.and 8P.M.ablated this temporal variation in aminopyrine t½ and aVd. Reversal of eating times (a 12‐hr fast before the 8P.M.aminopyrine dose and a 5A.M.meal before the 8A.M.dose) reversed the direction of the diurnal variation of aminopyrine t½ and aVd so that aminopyrine t½ and aVd were larger at 8A.M.but fasting for 32 or 44 hr did not alter the normal circadian rhythms of plasma 11‐hydroxycorticoids identified in our subjects at 8A.M.and 8P.M.Plasma protein binding of aminopyrine, determined at 8A.M.after a 12‐hr fast (29.8%), was higher than at 8P.M.(23.3%, p<0.05). Aminopyrine protein binding rose to 38.1% and 32.9% after a fast of 32 and 44 hr. Mean bioavailability and area under the curve of aminopyrine determined in plasma at 8A.M.and 8P.M.showed no diurnal change. As in saliva, aminopyrine concentrations in plasma revealed that mean aminopyrine t½ was 34% longer, mean aminopyrine aVd 33% larger, but mean aminopyrine Cl the same at 8P.M.as at 8A.M.These results suggest that meals decrease protein binding of aminopyrine, leading to increased aminopyrine aVd and t½, possibly due to increased tissue uptake of aminopyrine. Aminopyrine plasma concentrations after oral doses of 2, 4, and 8 mg/kg at 1‐wk intervals to each of six normal male subjects revealed dose dependence of aminopyrine t½ and hepatic first‐pass effect.Clinical Pharmacology and Therapeutics(1981)29,65–73;

ISSN:0009-9236    

DOI:10.1038/clpt.1981.12

年代:1981

数据来源: WILEY

摘要:

Fenbufen (γ‐oxo[1,1′‐biphenyl]‐4‐butanoic acid) is a nonsteroidal anti‐inflammatory analgesic that is metabolized to four major metabolites: γ‐hydroxy [1,1′‐biphenyl]‐4‐butanoic acid (II), [1,1′‐biphenyl]‐4‐acetic acid (III), 4′‐hydroxy [1,1′‐biphenyl]‐4‐acetic acid (IV), and γ,4′‐dihydroxy [1,1′‐biphenyl]‐4‐butanoic acid (V). Fenbufen and metabolites II and III circulate in plasma and are pharmacologically active; metabolites IV and V are normally excreted in urine. Single 800‐mg doses of fenbufen were safely administered to 10 healthy subjects and to 16 patients with varying degrees of renal insufficiency. Drug and metabolite concentrations in serum and urine were determined at intervals for 3 days. It was found that renal impairment altered the metabolic pattern of fenbufen. Although t½β was the same for fenbufen and II, their plasma levels fell. No change was found in the plasma levels of III. There was evidence of moderate cumulation in plasma of the two more polar urinary metabolites (IV, V) corresponding to the degree of renal insufficiency. The total of all five compounds excreted into the urine was diminished. To account for this, either biliary and gastrointestinal excretion increased or there may have been further hepatic biotransformation of the metabolites.Clinical Pharmaco

ISSN:0009-9236    

DOI:10.1038/clpt.1981.13

年代:1981

数据来源: WILEY

摘要:

Triazolam (T) is a new, potent hypnotic with a short duration of action in man. After an 0.88‐mg oral dose of T‐14C in six male subjects, mean recovery of14C radioactivity was 85% in urine and 8% in feces. The major urinary metabolites were α‐hydroxytriazolam (α‐HT) and 4‐hydroxytriazolam (4‐HT), accounting for 69% and 11% of the urinary14C, and these were mostly in conjugated form. α,4‐Dihydroxytriazolam and three dichlorotriazolylbenzophenone analogs were minor metabolites. At least 85% of the dose was rapidly absorbed; mean absorption half‐life (t½A) was 2.8 min. After reaching a mean peak plasma level (Cmax) of 8.8 ng/ml at mean time (tmax) of 1.3 hr, plasma T decreased rapidly with a mean elimination half‐life (t½E) of 2.3 hr. The remainder of the plasma14C consisted predominantly of glucuronides of α‐HT and 4‐HT. Mean plasma parameters for these metabolites were as follows: α‐HT‐glucuronide, t½E= 3.9 hr, tmax= 1.3 hr, Cmax= 6.1 ng/ml; 4‐HT‐glucuronide, ½E= 3.8 hr, tmax= 2.5 hr, Cmax= 6.1 ng/ml. Nonconjugated α‐HT and 4‐HT were present in plasma but in insufficient amounts for kinetic analysis. The results are consistent with the short duration of action.Clinical Pharmacology and Therapeu

ISSN:0009-9236    

DOI:10.1038/clpt.1981.14

年代:1981

数据来源: WILEY

摘要:

The peripheral vasoconstrictive effects of ergotamine, 0.25 mg intramuscularly and 2 mg sublingually, and a sublingual placebo were compared plethysmographically in 12 normal subjects. Both forms of ergotamine induced greater reductions than placebo in venous occlusion blood flow, systolic early ejection rate, systolic midtemporal ejection rate, systolic late runoff rate before aortic valve closure, diastolic runoff rate after aortic valve closure, and maximum and secondary pulse amplitudes. There were no significant differences between the ergotamine forms. The results indicate that the peripheral vasoconstrictive effects of ergotamine are equal after 0.25 mg intramuscularly and 2 mg sublingually. The two forms at those doses should be equally effective in migraine.Clinical Pharmacology and Therapeutics(1981)29,94–99; doi:10.1038/clpt.1981.

ISSN:0009-9236    

DOI:10.1038/clpt.1981.15

年代:1981

数据来源: WILEY

摘要:

Fentanyl kinetics was studied in two groups of six patients, one group undergoing surgery with and one without cardiopulmonary bypass; the latter served as the controls. Plasma fentanyl concentrations declined biexponentially in the control patients with an average half‐life (t½β) of 3.3 ± 1.1 hr, total plasma clearance of 11.2 ±3.4 ml/min/kg, and volume of distribution (Vdβ) of 3.2 ± 1.5 l/kg. The plasma concentration/time curves were severely disrupted during cardiopulmonary bypass but appeared to regain a log‐linear decay once bypass was complete. This elimination phase had a t½ of 5.2 ± 2.7 hr, longer than that in the control patients. Since fentanyl is eliminated primarily by hepatic metabolism, decreased liver plasma flow observed during and after bypass, as evidenced by a 30% decrease in indocyanine green clearance, may contribute to the extended t½. The prolonged t½ has clinical importance because of potentially prolonged effects and their relation to other drugs and the clinical management of the patient.Clinical Pharmacology and Therapeutics(1981)29,100–105; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1981.16

年代:1981

数据来源: WILEY

摘要:

The effect of low‐dose oral contraceptive steroids (OCS) on the kinetics of intravenous antipyrine was determined. Eight women (age, 23.1 ± 1.1 yr (x̄ ± SE); weight, 57.8 ± 2.2 kg) using low‐dose (≤ 50 µg) estrogen oral contraceptive steroids (OCS) on a long‐term basis were age‐ and weight‐matched with eight controls (age, 23.4 ± 0.8 yr; weight, 58.4 ± 2.1 kg) not using OCS. All were nonsmokers taking no other drugs. OCS subjects had a longer antipyrine elimination half‐life (t½β) than the controls (17.3 ± 1.6 and 10.5 ± 0.8 hr; p<0.005). Volume of distribution was similar for both groups (0.59 ± 0.02l/kg [OCS] and 0.58 ± 0.02l/kg). Total metabolic clearance of antipyrine was slowed in OCS subjects (0.41 ± 0.03 and 0.66 ± 0.05 ml/min/kg; p<0.001). Since volume of distribution and body weight are of the same order in both groups, prolongation of antipyrine t½β is the result of decreased total metabolic clearance. Thus, even low‐dose estrogen containing OCS may impair clearance of other drugs.Clinical Pharmacology and Therapeutics(1981)29,

ISSN:0009-9236    

DOI:10.1038/clpt.1981.17

年代:1981

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1981)29,111–123; doi:10.1038/clpt.1981.

ISSN:0009-9236    

DOI:10.1038/clpt.1981.18

年代:1981

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1981)29,124; doi:10.1038/clpt.1981.19

ISSN:0009-9236    

DOI:10.1038/clpt.1981.19

年代:1981

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1981)29,125–140; doi:10.1038/clpt.1981.

ISSN:0009-9236    

DOI:10.1038/clpt.1981.20

年代:1981

数据来源: WILEY