摘要:

Clinical Pharmacology and Therapeutics(1990)48,219–224; doi:10.1038/clpt.1990.1

ISSN:0009-9236    

DOI:10.1038/clpt.1990.142

年代:1990

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1990)48,224; doi:10.1038/clpt.1990.143

ISSN:0009-9236    

DOI:10.1038/clpt.1990.143

年代:1990

数据来源: WILEY

摘要:

The incidence of valproic acid hepatotoxicity has been reported to increase in patients who are receiving polytherapy. A minor valproic acid metabolite, 2‐propyl‐4‐pentenoic acid (4‐ene‐VPA), formed by a cytochrome P450‐mediated reaction, has been shown to be a potent inducer of microvesicular steatosis in rats. This study tested the hypothesis that formation of 4‐ene‐VPA would be increased in patients taking valproic acid with carbamazepine or with phenytoin but decreased with coadministration of an inhibitor of cytochrome P450 (the antiepileptic drug stiripentol in 300 to 1200 mg daily doses) in healthy subjects. Blood and urine samples in the studies were collected during a dosing interval at steady state. Valproic acid was assayed in plasma by capillary gas chromatography; valproic acid and 15 metabolites were measured in urine by gas chromatography/mass spectrometry. The formation clearance (CLf) of 4‐ene‐VPA was increased twofold in the valproic acid‐carbamazepine and valproic acid‐phenytoin groups. In the valproic acid/stiripentol studies, the CLfof 4‐ene‐VPA decreased by 32% in the 1200 mg/day stiripentol study. Similar findings were obtained at 600 and 300 mg/day stiripentol. These findings provide evidence supporting a role for cytochrome P450 in the formation of the hepatotoxic metabolite, 4‐ene‐VPA, in humans. The increased formation of 4‐ene‐VPA associated with carbamazepine and phenytoin is striking in relation to the epidemiologic finding of increased incidence of valproic acid–related hepatotoxicity during polytherapy with P450 inducers.Clinical Pharmacology and Therapeutics(1990

ISSN:0009-9236    

DOI:10.1038/clpt.1990.144

年代:1990

数据来源: WILEY

摘要:

One hundred fifty‐one patients with chronic cancer pain were studied during chronic treatment with oral morphine. Plasma concentrations of morphine and metabolites (M3G and M6G) were measured. The ratio of plasma morphine to metabolites was not affected by dose. Generalized linear interactive modeling analysis using morphine dose, age, sex, renal and hepatic dysfunction, and concomitant medication as explanatory variables accounted for 70% of the variance in plasma concentrations of morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G). Increasing morphine dose was a significant factor for increased plasma concentrations of morphine, M3G, and M6G. Other significant factors were: age greater than 70 years (increased M3G and M6G plasma concentrations), plasma creatinine>150 µmol/L (increased M3G and M6G plasma concentrations), male sex (decreased morphine and M6G plasma concentrations), raised creatinine plus coadministration of tricyclic antidepressants (increased M3G plasma concentrations), ranitidine (increased morphine plasma concentrations), and raised creatinine plus coadministration of ranitidine (increased M6G plasma concentrations).Clinical Pharmacology and Therapeutics(1990)48,236–244; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1990.145

年代:1990

数据来源: WILEY

摘要:

The effect of propafenone and its major metabolite 5‐hydroxy‐propafenone on ECG intervals was investigated in eight healthy extensive metabolizers after single oral (300 to 450 mg) and intravenous (35 to 50 mg) doses of propafenone in a single‐blind randomized trial. Peak serum concentrations were 278 ± 233 ng/ml (oral) and 295 ±131 ng/ml (intravenous). After oral administration peak 5‐hydroxy‐propafenone levels were 194 ± 65 ng/ml, whereas after intravenous dosing no metabolite was detected, except in one subject. Serum concentrations were related to effects by linear regression including a hypothetical effect‐site compartment in a pharmacokinetic‐pharmacodynamic model. Significant prolongations of ECG intervals were found in both sequences. Comparison of the two concentration‐effect data sets (intravenous, oral) revealed an additive effect of 5‐hydroxy‐propafenone in four of eight subjects for PQ interval and seven of eight subjects for QRS duration. We conclude that 5‐hydroxy‐propafenone exerts pharmacologic activity and could thus contribute to the antiarrhythmic effect of propafenone.Clinical Pharmacology and Therapeutics(1990)48,245–2

ISSN:0009-9236    

DOI:10.1038/clpt.1990.146

年代:1990

数据来源: WILEY

摘要:

Pharmacokinetic studies have been carried out with the oral iron chelator 1,2‐dimethyl‐3‐hydroxypyrid‐4‐one (L1). HPLC analysis of serum of a normal volunteer and seven transfusional iron loaded patients who ingested a 3 gm dose of L1 revealed that L1 was most probably absorbed from the stomach and was transferred to the blood with a half‐life of 0.7 to 32 minutes. L1 reached maximum concentration in the serum 12 to 120 minutes after administration with 85% to 90% elimination within the first 5 to 6 hours, with a half‐life of 47 to 134 minutes. L1 and its glucuronide metabolite were identified in serum and urine but not in feces. In most cases hydrolysis of 24‐hour urine samples with use of β‐glucuronidase resulted in almost complete recovery of the administered dose. Urinary iron excretion was proportional to the iron load but not to the serum or urine concentration of L1. The therapeutic efficiency of L1 can therefore be improved by repeated administration of 2 to 3 gm doses at least every 6 hours.Clinical Pharmacology and Therapeutics(1990)48,255–261; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1990.147

年代:1990

数据来源: WILEY

摘要:

Healthy human volunteers who intended not to breast feed were placed on a regimen of 100 mg oral flecainide every 12 hours for 5½ days beginning 1 day after parturition. Milk and blood samples were collected during the dosing period and for 2 days after the last dose. Concentrations of flecainide in milk and plasma were assayed by HPLC. Apparent steady‐state levels of flecainide in both milk and plasma were achieved in most cases by day 4 of the study. Highest daily average concentration of flecainide in milk ranged from 270 to 1529 ng/ml for the 11 subjects. Mean ± SD milk to plasma flecainide ratios were 3.7 ± 3.5, 3.2 ± 2.3, 3.5 ± 2.1, and 2.6 ± 0.7 on study days 2, 3, 4, and 5, respectively. After the last dose of flecainide, peak milk levels of the drug occurred at 3 to 6 hours and then declined monoexponentially. The half‐life for elimination of flecainide from milk was 14.7 ± 3.5 hours and is very similar to the plasma elimination half‐life of flecainide in healthy human subjects. The mean milk to plasma ratios for flecainide after the last dose were 2.3 ±1.0 and 2.9 ± 1.1 at 24 and 48 hours after the dose, respectively. Based on the pharmacokinetics of flecainide in infants, the expected average steady‐state plasma concentration of flecainide in a newborn infant consuming all of the milk production of its mother (~700 ml/day) would not be expected to exceed about 62 ng/ml. Because previous studies in infants and children has indicated very few toxic side effects attributed to flecainide at plasma levels ranging from 100 to 990 ng/ml, it appears that the risk to a suckling infant of ingesting toxic amounts of flecainide in human breast milk is very low.Clinical Pharmacology and Therapeutics(1990)48,262–267; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1990.148

年代:1990

数据来源: WILEY

摘要:

The pharmacokinetics of intravenously administered cefepime (1000 mg over 30 minutes) were studied in 5 healthy volunteers and 20 patients with various degrees of renal impairment. Cefepime concentrations in plasma, urine, and hemodialysate were assayed using reverse‐phase HPLC with ultraviolet detection. Mean peak plasma concentrations of cefepime at the end of 30‐minute infusion ranges from 63.5 to 73.9 μg/ml and were not affected by the degree of renal impairment. The half‐life of cefepime was approximately 2.3 hours in subjects with normal kidney function; it increased proportionately as renal function decreased. Significant linear relationships between total body clearance and creatinine clearance, as well as renal clearance and creatinine clearance, were observed. The mean volume of distribution at steady state in healthy volunteers was 20.5 liters and was not significantly altered in subjects with renal insufficiency. The mean cumulative urinary recovery of cefepime in healthy volunteers was 82.9% of the administered dose and significantly decreased in subjects with creatinine clearance less than 30 ml/min. Hemodialysis significantly shortened the elimination half‐life from 13.5 hours during the predialysis period to 2.3 hours during the dialysis period. Cefepime dosage should be reduced in proportion to the decline in creatinine clearance.Clinical Pharmacology and Therapeutics(1990)48,268–276; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1990.149

年代:1990

数据来源: WILEY

摘要:

Some recent epidemiologic studies have reported a nonlinear dose‐response in the relationship between coffee consumption and health risks, such that the risks increase disproportionately to the increase in dose. Assuming caffeine contributes to the adverse health effects of coffee, a possible explanation for the nonlinear dose‐response relationship is dose‐dependent metabolism of caffeine. We examined the hypothesis that under chronic dosing conditions the metabolism of caffeine is dose‐dependent. Nine healthy subjects were given, in randomized 5‐day treatment blocks, placebo, 4.2 (low) and 12 (high) mg/kg/day caffeine in decaffeinated coffee, in six divided doses spaced throughout the day. On the third day of each dosing period, 25 mg of stable‐isotope labeled caffeine (2‐13C, 1,3‐15N2) was given intravenously. Clearance of labeled caffeine fell from 0.118 (placebo treatment) to 0.069 (low dose;p<0.005) and to 0.054 (high dose;p<0.001) L/hr/kg. The formation and metabolite clearances of paraxanthine, the major primary metabolite of caffeine, also decreased comparing the low and high doses(p<0.05). We conclude that caffeine metabolism is dose‐dependent, resulting in nonlinear accumulation of methylxanthines in the body. Dose‐dependent metabolism of caffeine may explain in part why people who drink large amounts of coffee are at greater risk for cardiovascular disease.Clinical Pharmacology and Therapeutics(1990)48,277–285; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1990.150

年代:1990

数据来源: WILEY

摘要:

Exposure to certain environmental agents may induce a scleroderma‐like syndrome in a small proportion of individuals. Differences in susceptibility could involve metabolic activation of a protoxin, with affected patients having a greater converting ability. This possibility was investigated in 84 patients with scleroderma and 108 control subjects with in vivo probes of specific pathways of metabolism. Scleroderma was associated with reduced hydroxylating activity for dapsone and S‐mephenytoin, whereas the ability to hydroxylate debrisoquin and N‐acetyl dapsone was similar in both groups. Logistic regression confirmed these associations based on the shift in frequency distribution. Individuals who were poor metabolizers for mephenytoin and only modest N‐hydroxylators of dapsone had a tenfold increased risk of scleroderma(p= 0.008). Thus this combined metabolic impairment may be causally involved in the development of scleroderma or, alternatively, the disease may produce inhibition of selected metabolizing enzymes in a subset of patients.Clinical Pharmacology and Therapeutics(1990)48,286–295; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1990.151

年代:1990

数据来源: WILEY