Impact of theophylline dosing guidelines.
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Humans↗
Biomedical subjects
R L Slaughter
Publications and source records attributed to R L Slaughter.
Steroid-specific effects of ketoconazole on corticosteroid disposition: unaltered prednisolone elimination.
Ketoconazole inhibits the clearance of methylprednisolone by 60 percent and extends cortisol suppression beyond that produced by methylprednisolone alone. This study examined prednisolone pharmacokinetics and cortisol suppression in four healthy male volunteers following administration of prednisone 20 mg. Studies were performed with and without ketoconazole 200 mg po for six days. Blood samples were obtained serially over 24 hours and serum prednisone, prednisolone, and cortisol concentrations were determined by HPLC. Prednisolone clearance before and after ketoconazole therapy was not significantly different (160 +/- 38 vs. 148 +/- 23 mL/h/kg). In addition, no significant differences were found in mean residence time (5.03 +/- 0.69 vs. 6.18 +/- 1.77 h), terminal slope (0.23 +/- 0.03 vs. 0.19 +/- 0.05 h-1), or volume of distribution (0.79 +/- 0.11 vs. 0.84 +/- 0.12 L/kg). The ratio of cortisol area under the concentration versus time curve (AUC) 0-24 hours after prednisone administration to the AUC under baseline conditions was used as a measure of adrenal suppression. This ratio was not significantly different after prednisolone with and without ketoconazole (0.40 +/- 0.10 vs. 0.45 +/- 0.03). Renal excretion of prednisone and prednisolone was not significantly changed with ketoconazole. Based on this preliminary study, ketoconazole minimally alters prednisolone clearance in contrast to the significant ketoconazole-methylprednisolone interaction previously reported.
Administration, Oral↗
Comparison of assay procedures used to measure total and unbound concentrations of quinidine.
Individualized quinidine dosing through the assessment of serum concentrations is warranted because of the wide variability observed in its pharmacokinetic behavior and its reported narrow therapeutic index. The free fraction of quinidine also varies widely. Thus the development of procedures that could be widely used to determine quinidine free concentrations would be highly desirable. It was the purpose of this study to evaluate several procedures available to determine total serum quinidine concentrations (rate nephelometry [ICS], homogenous enzyme immunoassay [EMIT], and high-performance liquid chromatography [HPLC]). Furthermore, in samples from 46 patients, equilibrium dialysis and ultrafiltration procedures were compared for their ability to estimate quinidine free fraction. Finally, unbound concentrations of quinidine were compared using a modified EMIT procedure and a standard HPLC method to quantitate quinidine in ultrafiltrates from patient samples. For the measurement of total quinidine concentrations, reasonable agreement was seen when EMIT and ICS systems were compared with HPLC (ICS = 1.03.HPLC + 0.96, r = 0.93; EMIT = 1.08.HPLC + 0.38, r = 0.93) The mean errors, however, for these procedures were high (ICS +70 percent, range +7 to +233 percent; EMIT +35 percent, range 0 to 110 percent). Quinidine free fractions (QFF) determined by equilibrium dialysis (E) and ultrafiltration (U) showed good agreement (QFF(U) = 1.11.QFF(E) +0.0; r = 0.96). Unbound quinidine concentration determined by EMIT analysis of ultrafiltrate substantially overestimated the values obtained by HPLC analysis (mean error by EMIT 104 +/- 59 percent). It is concluded that HPLC is the method of choice for determining both total and unbound serum quinidine concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Chromatography, High Pressure Liquid↗
Use of concurrent monitoring and a preprinted note to modify prescribing of i.v. cimetidine and ranitidine in a teaching hospital.
The use of concurrent monitoring and an informational note to modify physician prescribing of i.v. cimetidine and ranitidine is described. The study population consisted of all patients for whom i.v. cimetidine and ranitidine therapy was prescribed by house-staff physicians at an 850-bed, tertiary-care, university-affiliated hospital during February, March, and April 1987. Phase 1 of the trial consisted of an initial drug-use review of all eligible patients receiving therapy. In phase 2, the study population was divided into an intervention group and a control group. When therapy could be changed from the i.v. to the oral or nasogastric (NG) route of administration, an informational note was placed in the chart of the patients in the intervention group. Patients in the control group were also assessed daily for the appropriateness of conversion to oral or NG therapy. The following outcome measures were used to test the effectiveness of the intervention in modifying physician prescribing: mean number of i.v. doses and days of i.v. therapy per patient and mean number of inappropriate i.v. doses and days of i.v. therapy per patient. The drug acquisition costs for both groups were also analyzed. A total of 233 patients were monitored during the study period. The percentage of patients who did not receive oral therapy as soon as possible was not significantly different between the intervention (55%) and control (58%) groups. Patients in the intervention group received three to six fewer i.v. doses than patients in the control group and three to six additional oral doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Simultaneous analysis of methylprednisolone hemisuccinate, cortisol and methylprednisolone by normal-phase high-performance liquid chromatography in human plasma.
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Adult↗
Differential effect of pentobarbital and chloralose in anesthetic doses on the serum protein binding of lidocaine in the dog.
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Anesthesia↗
The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine.
1. The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine based upon measurements of total and unbound serum concentrations were determined after a single dose (400 mg) and at steady state (200 mg every 6 h). 2. The oral clearance (7.6 +/- 1.9 vs 4.8 +/- 2.0 ml min-1 kg-1; P less than 0.05) and renal clearance (1.2 +/- 0.3 vs 0.63 +/- 0.25 ml min-1 kg-1; P less than 0.005) or quinidine were lower during steady state than after the single dose. 3. The area under the serum concentration vs time curve (AUC) of 3-hydroxyquinidine was greater at steady state than after the single dose (2.0 +/- 0.7 vs 3.0 +/- 0.6 mg l-1 h; P less than 0.05) and its renal clearance was less (3.0 +/- 1.1 vs 1.54 +/- 0.38 ml min-1 kg-1; P less than 0.05). 4. The slope of the relationship between quinidine concentration and change in QTc interval was greater at steady state (40.1 +/- 21.7 vs 72.2 +/- 41.7 ms/(mg l-1); P less than 0.05).
Adult↗
Lack of effect of atenolol on the pharmacokinetics of theophylline.
The effects of 3 days of pretreatment with cardioselective doses of atenolol on theophylline pharmacokinetics were determined. Nine healthy nonsmoking male volunteers received 6 mg kg-1 i.v. aminophylline under baseline conditions and after both 50 mg day-1 and 100 mg day-1 atenolol. Theophylline clearance, volume of distribution and half-life were not influenced by atenolol pretreatment. These data indicate that cardioselective doses of atenolol do not alter the pharmacokinetics of theophylline.
Adult↗
The effects of a beta-2 selective adrenergic agonist and a beta-nonselective antagonist on theophylline clearance.
Beta-adrenergic agonists and antagonists have been shown to alter theophylline pharmacokinetics. It was the purpose of this study to characterize further the effects that terbutaline and propranolol have on theophylline disposition. In nine healthy male volunteers, mean parameters for theophylline disposition did not change after four days of terbutaline (5 mg q8h). Theophylline clearance, however, did change within the subjects. Clearance increased in five subjects, decreased in three, and remained unchanged in one volunteer. Pretreatment with four days of terbutaline (5 mg q8h) and propranolol (60 mg q8h) significantly decreased mean theophylline clearance (60.1 +/- 12.9 vs 40.6 +/- 9.9 mL/min/1.73m2; P less than .01) increased half-life (8.37 +/- 1.77 vs 12.32 +/- 2.70 hours; P less than .05), and increased postinfusion theophylline concentration (13.5 +/- 2.7 vs 18.95 +/- 2.5 micrograms/mL; P less than .001). In five subjects theophylline clearance increased after terbutaline pretreatment (64.6 +/- 13.0 vs 75.0 +/- 13.9 mL/min/1.73m2). The percentage increase ranged from 3.9 to 28.5%. These subjects were restudied after receiving propranolol alone (60 mg q8h). Comparison between the propranolol and terbutaline study and the propranolol alone study indicated no mean change in clearance in these five subjects (41.8 +/- 12.7 vs 36.1 +/- 5.1 mL/min/1.73m2). Thus it appears that the changes observed in these five subjects after terbutaline pretreatment may have been random in occurrence as has been shown to occur with theophylline disposition and are not related to terbutaline pretreatment. It is concluded that beta-2 adrenergic stimulation does not alter theophylline pharmacokinetics, whereas nonselective beta-adrenergic antagonism profoundly affected theophylline disposition. This is an additional reason not to use propranolol in patients who receive theophylline.
Adrenergic beta-Agonists↗
Total and unbound concentrations of quinidine and 3-hydroxyquinidine at steady state.
Recent reports indicate that the metabolite of quinidine, 3-hydroxyquinidine, is pharmacologically active. It was the primary purpose of this study to determine total and unbound concentrations of quinidine and 3-hydroxyquinidine in 25 patients receiving quinidine for therapeutic purposes. At the peak, total quinidine and 3-hydroxyquinidine concentrations were 2.7 +/- 1.2 micrograms/ml and 0.57 +/- 0.33 micrograms/ml, respectively, and at the trough they averaged 2.0 +/- 0.91 micrograms/ml and 0.44 +/- 0.25 micrograms/ml. Interestingly, the unbound 3-hydroxyquinidine concentration frequently exceeded the unbound quinidine concentration, averaging 0.30 +/- 0.28 micrograms/ml at the peak and 0.22 +/- 0.14 micrograms/ml at the trough. Quinidine concentrations averaged 0.24 +/- 0.15 micrograms/ml and 0.18 +/- 0.12 micrograms/ml. The ratio of unbound 3-hydroxyquinidine: quinidine was significantly influenced by the unbound clearance of quinidine (r = 0.66). At low clearance values concentrations of both substances were elevated, with the quinidine concentration consistently exceeding that of 3-hydroxyquinidine. In contrast, at high clearance values 3-hydroxyquinidine concentrations were elevated and consistently exceeded the quinidine concentration. Thus, when quinidine concentrations are used to monitor the pharmacodynamic effect of quinidine, it is most appropriate to evaluate unbound concentrations of both quinidine and 3-hydroxyquinidine.
Aged↗
Relationship of serum antibiotic concentrations to nephrotoxicity in cancer patients receiving concurrent aminoglycoside and vancomycin therapy.
Methicillin-resistant coagulase-negative staphylococci have become increasingly responsible for febrile episodes in cancer patients, often necessitating the addition of vancomycin to an aminoglycoside-containing broad-spectrum antibiotic regimen. A total of 229 courses of antibiotic therapy in 229 patients were evaluated for nephrotoxicity associated with the administration of an aminoglycoside and/or vancomycin. The incidence of nephrotoxicity observed in patients administered an aminoglycoside (Group A) was 18 percent; vancomycin (Group B) 15 percent; and an aminoglycoside concurrently with vancomycin (Group C) 15 percent. The following pharmacokinetic/dosing factors were significantly associated with increased nephrotoxicity in the groups: baseline serum creatinine level, mean daily dose during the first three days of therapy (Group B), and elevated serum trough aminoglycoside or vancomycin concentrations (2 micrograms/ml or more or 10 micrograms/ml or more, respectively). No cumulative nephrotoxicity was demonstrated with the concurrent administration of vancomycin and an aminoglycoside. A higher incidence of nephrotoxicity was seen in Group C (42 percent) and Group B (27 percent) patients, in whom trough serum vancomycin concentrations were 10 micrograms/ml or more.
Aminoglycosides↗
Intraindividual variability in theophylline pharmacokinetics in subjects with mild/moderate asthma.
Intrasubject variability in theophylline pharmacokinetics was assessed in six subjects with mild/moderate asthma. On four occasions, each separated by a minimum of 3 weeks, a 6 mg/kg intravenous aminophylline dose was infused during 30 minutes, and multiple blood samples were obtained thereafter. The pharmacokinetic parameters of clearance (Cl), volume of distribution, and half-life were determined by noncompartmental analysis. There was evidence for within-subject variability in these parameters. In comparison to the first study day, Cl changed by greater than 15% in all but one subject and by greater than 25% in two of six subjects. Changes in half-life exceeding 25% of the value observed on the first study day occurred in three of six subjects. Within-subject coefficient of variation for Cl was 14.9% (range 3.9% to 33.3%) and 14.4% (range 5.8% to 24.3%) for half-life. Volume of distribution, however, was a more stable parameter with a within-subject coefficient of variation of 7.2% (range 2.3% to 11.1%). Thus, within-subject changes in the pharmacokinetics of theophylline do exist over time. These data suggest that close monitoring of patients receiving theophylline is warranted, particularly when theophylline concentrations are maintained at either extreme of the therapeutic range.
Adult↗
Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol.
The effects of ketoconazole and methylprednisolone on endogenous cortisol were studied in eight normal subjects. Intravenous methylprednisolone sodium succinate was given alone in doses of 15 or 30 mg. The methylprednisolone dose was reduced by 57% when ketoconazole was administered chronically for 1 week to seek equivalent methylprednisolone AUCs by compensating for the expected reduction in methylprednisolone clearance. Ketoconazole decreased clearance by 46% and increased mean residence time by 37%. The ratio of the cortisol AUC during each drug treatment compared with baseline conditions was used to assess the net extent and duration of cortisol suppression. This cortisol AUC ratio was reduced from 0.45 (methylprednisolone) to 0.39 (methylprednisolone plus ketoconazole), suggesting that ketoconazole modestly enhanced (P less than 0.01) cortisol suppression. Based on the reduction in methylprednisolone clearance and cortisol AUC by ketoconazole, a 50% lower dose of methylprednisolone during concomitant therapy with ketoconazole is recommended.
Adult↗
Lack of effect of smoking on the metabolism and pharmacokinetics of quinidine in patients.
The urinary metabolite profile of quinidine and the oral clearance of this drug were studied under steady state conditions in five smoking and nine non-smoking patients. No significant differences were observed in the urinary recovery of unchanged quinidine, 3S-3-hydroxyquinidine, 2'-oxoquinidinone or quinidine-N-oxide between smokers and non-smokers. In addition, the plasma clearance of quinidine was not affected by the smoking status of subjects. These results suggest that cigarette smoke does not induce any of the main pathways for quinidine metabolism in a typical patient population and that the consideration of smoking status is of little utility in aiding in the selection of initial dosage regimens for this drug.
Aged↗
Pharmacokinetics of ketoconazole administered intravenously to dogs and orally as tablet and solution to humans and dogs.
The single-dose pharmacokinetics and bioavailability of three ketoconazole formulations were evaluated using HPLC in five healthy human volunteers and six male mongrel dogs. The human volunteers received 400 mg po of ketoconazole as tablet (Ktab) and solution (Ksol) formulations. The dogs received 400 mg po of Ktab and Ksol, and 376 mg iv of an intravenous dose (Kiv). In humans the AUC value for Ksol (62.21 +/- 21.2 microgram X h/ml; mean +/- SD) was significantly greater than for Ktab (50.0 +/- 15.2 micrograms X h/ml; p less than 0.05). Peak serum concentrations (Cmax), time to peak serum concentrations (tmax), t1/2, and the terminal elimination rate constant (kel) did not differ between Ktab and Ksol. This suggests that the administration of Ksol may be a useful alternative to dosage increases in situations where low bioavailability of ketoconazole in tablet form is suspected. The mean systemic clearance (CLs) of Kiv in dogs was 2.74 +/- 1.10 mL/min/kg, the volume of distribution at steady state (Vdss) was 0.72 +/- 0.28 L/kg, and the half-life was 2.7 +/- 1.6 h. Considerable variability was seen in the AUC of ketoconazole, particularly with the oral preparations. The absolute bioavailability of Ktab was 0.50 +/- 0.38, which did not differ statistically from that of Ksol, 0.56 +/- 0.23. The Ksol showed less variability in AUC, Cmax, and F values than did Ktab, and two dogs with low bioavailability with Ktab (0.04 and 0.07) had substantially greater bioavailability with Ksol (F = 0.96 and 0.57, respectively). Evaluation of Kiv in dogs confirms decreased bioavailability from orally administered tablet formulations of ketoconazole.
Administration, Oral↗
Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion.
The disposition of methylprednisolone was examined in six normal subjects after the injection of 20 mg iv methylprednisolone sodium succinate. Disposition studies were performed both without and with ketoconazole, 200 mg/day, for 6 days. Ketoconazole increased the methylprednisolone AUC and mean residence time (by 135% and 66%, respectively) and decreased clearance (60%), the terminal phase slope, and the volume of distribution. These findings are typical of macrolide antibiotic alteration of methylprednisolone disposition and consistent with reports of inhibition of drug metabolism by ketoconazole. Methylprednisolone reduced the 24-hour cortisol AUC by 44%, but morning cortisol concentrations returned to normal. Ketoconazole with methylprednisolone further reduced the 24-hour cortisol AUC and suppressed morning cortisol concentrations. Thus ketoconazole inhibits methylprednisolone disposition and extends the adrenal suppression effects of this corticosteroid.
Adult↗
The pharmacokinetics of meperidine in acute trauma patients.
Traumatic injury has the potential to alter the hepatic clearance and hence the efficacy and toxicity of drugs by a variety of mechanisms. These include changes in hepatic microsomal enzyme activity, hepatic blood flow rate, and plasma protein binding. Unfortunately, there have been few pharmacokinetic studies in trauma patients. Thus, few data are available to provide guidance in drug regimen design for these individuals. Meperidine clearance was therefore evaluated in patients with traumatic injury and an effort was made to identify physiologic and/or clinical predictors of clearance which could facilitate initial dosage selection. Meperidine total body clearance (TBC) was determined on 12 occasions at steady state following IM administration of meperidine to nine severely injured nonseptic trauma patients with normal renal and hepatic function. TBC of this drug averaged 684 +/- 206 ml/min (mean +/- SD) and was highly correlated with ideal body weight (IBW) (r2 = 0.735; F = 27.75; n = 12; p less than 0.01). The serum concentration of the acute phase reactant protein, alpha 1 acid glycoprotein (AGP), which binds meperidine and many other basic drugs increased strikingly in an apparent linear manner at a rate of 27 mg/dl/day up to 9 days after the traumatic event (r2 = 0.828; F = 42.30; n = 12; p less than 0.01). However, this increase in binding protein concentration was not associated with an alteration in meperidine TBC as has been reported for other drugs. It is concluded that IBW may be a useful guide initial dosage selection of meperidine in acute trauma patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Intrasubject variability of theophylline clearance in a morbidly obese patient.
It is well appreciated that theophylline pharmacokinetics exhibits wide intersubject variation. Within-subject changes in clearance have been generally reported in patients with acute exacerbations of disease states such as cor pulmonale or heart failure. Apparent random changes in theophylline clearance within the same patient have recently been reported. This report describes a case of suspected changes in the clearance of theophylline in a morbidly obese patient (250 kg) over a two-month period of time. Frequent dosage adjustments were required to maintain theophylline concentrations within the range of 8.2 to 27.3 micrograms/ml. Possible explanations for these changes included hypoxia and medically induced starvation. Daily theophylline doses ranged from 600 to 1600 mg/d. It is concluded that in some individuals, within-subject changes in theophylline clearance can be substantial, thus requiring frequent monitoring of theophylline concentration.
Female↗