摘要:

Clinical Pharmacology and Therapeutics(1989)45,337–339; doi:10.1038/clpt.1989.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.38

年代:1989

数据来源: WILEY

摘要:

Steady‐state plasma levels of doxorubicin and doxorubicinol were analyzed in 32 patients with advanced cancer, each of whom was given doxorubicin by long‐term continuous infusion at progressively increasing infusion rates. Patients received doxorubicin for 2 to 50 weeks at rates of 0.2 to 6.1 mg/m2/day. Dose‐limiting stomatitis and leukopenia were observed. The mean maximum steady‐state doxorubicin concentration was 6.04 ng/ml at a mean maximum infusion rate of 3.92 mg/m2/day. Clearance mechanisms did not appear to be saturated at the durations or infusion rates used in this study. The maximum steady‐state doxorubicin level and the In (initial WBC) were significant correlates of the In (nadir WBC)(p= 0.002 and 0.02, respectively). A model was constructed according to these two parameters that significantly describes In (nadir WBC)(p= 0.001). Neither age, infusion rate, nor doxorubicinol level correlated with nadir WBC. Stomatitis did not correlate with any of these parameters. The demonstration of this pharmacodynamic relationship highlights the potential importance of pharmacologic data collection in ongoing attempts to predict the clinical effects of anticancer drugs.Clinical Pharmacology and Therapeutics(1989)45,340–347; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1989.39

年代:1989

数据来源: WILEY

摘要:

Single oral 10 mg doses of diazepam and demethyldiazepam were given on different occasions to 16 healthy subjects. The subjects included four poor hydroxylators of debrisoquin and three poor hydroxylators of mephenytoin. There was a correlation between the total plasma clearance of diazepam and demethyldiazepam(rs= 0.83;p<0.01). There was no relationship between benzodiazepine disposition and debrisoquin hydroxylation. Poor hydroxylators of mephenytoin had less than half the plasma clearance of both diazepam(p= 0.0008) and demethyldiazepam(p= 0.0001) compared with extensive hydroxylators of mephenytoin. The plasma half‐lives were longer in poor hydroxylators than they were in extensive hydroxylators of mephenytoin for both diazepam (88.3 ± SD 17.2 and 40.8 ± 14.0 hours;p= 0.0002) and demethyldiazepam (127.8 ± 23.0 and 59.0 ± 16.8 hours;p= 0.0001). There was no significant difference in volume of distribution of the benzodiazepines between the phenotypes. This study shows that the metabolism of both diazepam (mainly demethylation) and demethyldiazepam (mainly hydroxylation) is related to the mephenytoin, but not to the debrisoquin, hydroxylation phenotype.Clinical Pharmacology and Therapeutics(1989)45,348–355; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1989.40

年代:1989

数据来源: WILEY

摘要:

Eleven healthy volunteers received a single intravenous dose of diazepam (0.15 mg/kg), midazolam (0.1 mg/kg), and placebo by 1‐minute infusion in a double‐blind, three‐way crossover study. Plasma concentrations were measured during 24 hours after dosage, and the electroencephalographic (EEG) power spectrum was simultaneously computed by fast‐Fourier transform to determine the percentage of total EEG amplitude occurring in the 13 to 30 Hz range. Both diazepam and midazolam had large volumes of distribution (1.2 and 2.3 L/kg, respectively), but diazepam's half‐life was considerably longer (33 versus 2.8 hours) and its metabolic clearance lower (0.5 versus 11.0 ml/min kg) than those of midazolam. EEG changes were maximal at the end of the diazepam infusion and 5 to 10 minutes after midazolam infusion. Percent 13 to 30 Hz activity remained significantly above baseline until 5 hours for diazepam but only until 2 hours for midazolam. For both drugs, EEG effects were indistinguishable from baseline by 6 to 8 hours, suggesting that distribution contributes importantly to terminating pharmacodynamic action. The relationship of EEG change to plasma drug concentration indicated an apparent EC50value of 269 ng/ml for diazepam as opposed to 35 ng/ml for midazolam. However, Emaxvalues were similar for both drugs (+19.4% and + 21.3%, respectively).Clinical Pharmacology and Therapeutics(1989)45,356–365; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1989.41

年代:1989

数据来源: WILEY

摘要:

The impact of ketoconazole (200 mg for 7 days) on the kinetics of oral prednisone and intravenous prednisolone and on the apparent activity of the 6 β‐hydroxylase was investigated in 10 healthy volunteers. The ratio of urinary 6β‐OH‐cortisol/17‐OH‐corticosteroids declined by>50% and the urinary excretion of 6β‐OH‐prednisolone decreased more than twofold in all subjects. The decline of the activity of the 6β‐hydroxylase was associated with impaired metabolic and renal clearances of total and unbound prednisolone. The ratios of the AUCs of prednisolone/prednisone after oral prednisone and intravenous prednisolone were independent of the administration of ketoconazole, suggesting that the enzymes responsible for the interconversion of prednisolone ⇄ prednisone were not affected by ketoconazole. Thus ketoconazole inhibits 6β‐hydroxylase and increases the exposure of the body to the biologically active unbound prednisolone after oral prednisone or intravenous prednisolone.Clinical Pharmacology and Therapeutics(1989)45,366–37

ISSN:0009-9236    

DOI:10.1038/clpt.1989.42

年代:1989

数据来源: WILEY

摘要:

Pharmacokinetics of ornidazole, a nitroimidazole derivative, was investigated after intravenous injection in 3 groups of 10 patients with different hepatic diseases: hepatitis, noncholestatic cirrhosis and extrahepatic cholestasis. Plasma concentrations of ornidazole and its two major hydroxylated metabolites, M1 [α‐(chloromethyl)‐2‐hydroxymethyl‐5‐nitroimidazole‐ 1‐ethanol] and M4 [3‐(2‐methyl‐5‐nitroimidazole 1‐yl)‐1,2‐propane diol]were measured by HPLC assay. As a consequence of a decreased clearance (26% to 48%), the half‐life and MRT are increased in all patients by 19% to 38% when compared with healthy volunteers. No clear difference could be established between the different groups. The volume of distribution remains the same in all patients and controls except those suffering from cancer. As previously shown in patients with severe liver cirrhosis, both metabolites accumulate in plasma as a result of decreased elimination; formation is no longer the rate‐limiting step of their kinetics. This metabolite accumulation is in part due to decreased biliary excretion and to hepatocellular failure.Clinical Pharmacology and Therapeutics(1989)45,

ISSN:0009-9236    

DOI:10.1038/clpt.1989.43

年代:1989

数据来源: WILEY

摘要:

Healthy young black men and white men received single intravenous doses of metoprolol (0.07 mg/kg) or participated in an isoproterenol sensitivity study before and after metoprolol (0.07 mg/kg followed by 50 µg/min) in a randomized, crossed‐over fashion. Noncompartmental pharmacokinetic parameters were calculated. The dose of isoproterenol versus change in heart rate response curves were constructed, and comparisons of dose ratio, ED50, Emax, and Ka, with the apparent association constant for metoprolol binding to β1receptors, were made. There were no pharmacokinetic differences observed between the groups. The predicted Emaxfor the black group was 52.7 ± 8.7 beats/mm at a metoprolol concentration of 29.8 ± 6.1 ng/ml, which was higher(p<0.05) than that in the white group, i.e., 43.7 ± 7.3 beats/min at a concentration of 27.6 ± 9.1 ng/ml. There were no differences in dose ratio, ED50, or Ka. The racial differences in β1‐receptor responses to exogenous isoproterenol following metoprolol can simply be explained by an increase in β1‐receptor activity in the black subjects, assuming homogeneity in cardiac β2‐receptor responses.Clinical Pharmacology and Therapeutics(1989)45,380–386; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.44

年代:1989

数据来源: WILEY

摘要:

Right ventricular repolarization and refractoriness were studied during continuous infusion of lidocaine in patients with coronary artery disease. Compared with baseline the duration of monophasic action potential was shortened(p<0.01) at constant and premature stimulation. Early premature action potentials were less shortened(p<0.05). Therefore the difference between the longest and shortest action potential duration elicited 2 to 150 msec after refractoriness decreased during lidocaine infusion(p<0.01). The right ventricular effective refractory period was shortened similarly to the action potential duration. Lidocaine did not change the conduction of constant paced beats, whereas the more rapid conduction of the midrange premature beats was inhibited(p<0.01). The inhibition of premature conduction 50 to 150 msec from the right ventricular effective refractory period may be attributed to the effect of lidocaine on the rate‐dependent recovery from inactivation. The effect on the restitution curve indicates that lidocaine may influence the dispersion of premature action potentials in human beings.Clinical Pharmacology and Therapeutics(1989)45,387–395; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1989.45

年代:1989

数据来源: WILEY

摘要:

The effect of application site and frequency on the systemic absorption of topical minoxidil was studied in 52 normal men. Subjects received 1 ml 3% minoxidil solution applied four, six, or eight times daily to the scalp or two, four, six, or eight times daily to the chest for 14 days. Serum and urine were collected and analyzed for minoxidil. No systemic minoxidil accumulation occurred from increasing application frequency to the scalp. Trends in the chest data suggest that absorption may have been lower with the twice‐daily regimen. Absorption through the scalp and chest were similar for the lower‐frequency regimens; however, trends in the eight‐times‐a‐day regimens suggest that absorption may have been somewhat greater from application to the scalp. Systemic minoxidil accumulation resulting from frequent application is unlikely. The initial dose probably saturates the skin for a period of time longer than the dosing intervals examined.Clinical Pharmacology and Therapeutics(1989)45,396–402; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1989.46

年代:1989

数据来源: WILEY

摘要:

A number of studies have demonstrated that lipophilic β‐adrenoceptor blocking agents, eliminated almost exclusively by hepatic metabolism, are stereoselectively metabolized in human beings. Previous studies in our laboratory have demonstrated that pindolol, a β‐adrenoceptor blocking agent of intermediate lipophilicity that is eliminated by both hepatic metabolism and renal excretion, is eliminated stereoselectively in the kidney. In the present study we examined the pharmacokinetics of the enantiomers of atenolol, a hydrophilic cardioselective β‐adrenoceptor blocking agent that is eliminated almost exclusively by the kidney. A single 100 mg oral dose of racemic atenolol was administered to six healthy adult men. Concentrations ofd‐ andl‐atenolol in plasma and urine were measured by a stereospecific HPLC analytic procedure. In each subject the peak concentration ofl‐atenolol was greater than the peak concentration ofl‐atenolol (mean ± SD of 420 ± 81 ng/ml vs 366 ± 61 ng/ml;p<0.05). The peak concentration of both enantiomers was reached at the same time in each subject (between 2 and 3 hours). The renal clearances ofd‐ andl‐atenolol were not significantly different (109.7 ± 33.5 ml/min vs 112.5 ± 36.7 ml/min), probably because the major route of renal elimination is glomerular nitration. The half‐lives ofdandl‐atenolol were not significantly different (mean ± SD of 4.6 ± 1.1 hours vs 5.2 ± 0.9 hours). However, both the AUC and the amount excreted unchanged in the urine in 24 hours Ae [0–24]) were significantly greater ford‐atenolol than forl‐atenolol (p<0.05). These data suggest that the bioavailability of atenolol is stereoselective. Although the magnitude of the stereoselectivity was small and the ratio of the active to inactive enantiomer did not differ greatly from unity, the mechanism responsible for the stereoselectivity is of interest in light of the very low metabolic clearance of atenolol. A possible mechanism that may account for the stereoselective bioavailability is stereoselective active absorption.Clinical Pharmacology and Therapeutics(19

ISSN:0009-9236    

DOI:10.1038/clpt.1989.47

年代:1989

数据来源: WILEY