Dose dependent pharmacokinetics of theophylline: Michaelis-Menten parameters for its major metabolic pathways.

Dose Dependency for pharmacokinetics of theophylline and the formation of its major metabolites, 3-methylxanthine (3-MX); 1-methyluric acid (1-MU); 1,3-dimethyluric acid (DMU), were examined by administering three single oral doses (250, 375, 500 mg) of theophylline to six healthy adult volunteers. The serum and urine concentrations of theophylline and the metabolites in serum and urine were determined by high-performance liquid chromatography. Total clearance of theophylline decreased and its half life increased over the range of doses administered (p<0.01). There was a significant dose related decrease in the fractional recovery of 3-MX and 1-MU (p<0.001) and a dose related increase in fractional excretion of DMU and unchanged theophylline (p<0.01 and p<0.001 respectively). No significant dose related changes were observed in the renal clearance of 3-MX, 1-MU and DMU, indicating linear urinary excretion kinetics of the metabolites. Theophylline metabolic clearance to 3-MX as well as to 1-MU decreased with increasing dose but clearance to DMU remained unnaffected by the size of dose. The individual Michaelis-Menten parameters Km and Vmax were estimated for six subjects receiving three different single doses. The Km values for theophylline metabolism to 3-MX, 1-MU and DMU were 2.4+/-0.6, 5.1+/-1.8+/- and 112.3+/-36.8 mg/L respectively and the Vmax values were 3.5+/-0.7, 7.5+/-2.6 and 112.3+/-36.8 mg/hr respectively. The Km values for the N-demethylation pathways (3MX and 1-MU) were lower corresponding to therapeutic serum concentrations of drug. These results suggest that the elimination kinetics of theophylline is nonlinear in the human in the therapeutic range of serum concenntrations and can be explained by saturable formation kinetics of 3-MX and 1-MU. In contrast to previous studies we didn't find obvious indication for nonlinear formation of DMU at therapeutic concentration range.     

Dose dependent pharmacokinetics of prednisolone

Summary The pharmacokinetics of prednisolone elimination have been studied in both arthritic patients and normal volunteers using tritiated prednisolone alone, and in conjunction with unlabelled prednisolone in doses of 0.15 mg·kg^–1 and 0.3 mg·kg^–1 body weight. With increasing dose there is prolongation of the plasma half-life and increase in the volume of distribution and plasma clearance of prednisolone. It is proposed that these changes in pharmacokinetic parameters may be associated with non-linear binding of the steroid to plasma proteins.     

Dose dependent pharmacokinetics of midazolam

Summary The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the C_max and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t_1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This ist not expected to have any clinical significance under the conditions of therapeutic use.     

Dose dependent pharmacokinetics of albendazole in human

Pharmacokinetics of albendazole sulphoxide (ABZ-SO) in three different single oral doses of albendazole (ABZ) (400, 800 and 1200 mg) was studied in 10 healthy human volunteers in a double blind three-way crossover design. The serum levels of albendazole main metabolite, albendazole sulphoxide (ABZ-SO), were analysed by a modified high-pressure liquid chromatography method. (ABZ is not detectable in biological fluids itself.)For ABZ-SO, there was no significant difference in the biological half life, normalized serum peak concentration (C(max-ABZ-SO)/Dose(ABZ)), time to reach peak concentration (T(max)) and mean residence time (MRT), whereas apparent clearance (Cl(p)/F), apparent distribution volume (V(d)/F), normalized area under the serum concentration-time curve (AUC(ABZ-SO)/Dose(ABZ)) and normalized area under the first moment curve (AUMC(ABZ-SO)/Dose(ABZ)) of albendazole main metabolite (ABZ-SO) were statistically different at different doses of the parent drug, resulting in substantially lower serum concentration and thereafter AUC(ABZ-SO)/Dose(ABZ) and AUMC(ABZ-SO)/Dose(ABZ) in higher doses. These observations indicate dose dependent pharmacokinetics of albendazole (observed for ABZ-SO), which were explained on the basis of a change in fraction of dose absorbed (F) as a result of slow and incomplete dissolution of the main drug in the GI tract.     

Dose dependent pharmacokinetics of prednisone and prednisolone in man

Six healthy male volunteers were given 5, 20, and 50 mg of oral prednisone and 5, 20, and 40 mg doses of intravenous prednisolone. Plasma and urine concentrations of prednisone and prednisolone were determined by HPLC, and the binding of prednisolone to plasma proteins was measured by radioisotopic and equilibrium dialysis techniques. The pharmacokinetics of both oral prednisone and intravenous prednisolone were dose-dependent. The mean oral dose plasma clearances of prednisone ranged from 572 ml/min/ 1.73 m ² for the 5mg dose to 2271 ml/min/1.73 m ² for the 50 mg dose. Changes in prednisone half-life were insignificant, but increases in the half-life of its metabolite were dose-dependent. The systemic plasma clearance of i.v. prednisolone was dose-dependent and increased from 111 to 194 ml/min/1.73 m ² over the 5 to 40 mg i.v. dosage range. The steady-state volume of distribution also increased, but little change in mean transit time and half-life was found. The binding of prednisolone to plasma proteins was markedly concentration-dependent, and a two compartment, nonlinear equation was used to characterize the effective binding of prednisolone to transcortin and albumin. The apparent pharmacokinetic parameters of protein-free and transcortin-free prednisolone were relatively constant with dose. The interconversion of prednisone and prednisolone varied with time and dose, although prednisolone concentrations dominated by 4-to 10-fold over prednisone. In urine, 2–5% of either administered drug was excreted as prednisone and 11–24% as prednisolone. The apparent renal clearances of both steroids were also nonlinear and unrelated to protein binding. These studies indicate that the pharmacokinetics of prednisone and prednisolone are dose-dependent and that protein binding does not fully explain their apparent nonlinear distribution and disposition.This work was supported in part by Grant 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.     

Transdermal fentanyl: pharmacokinetics and preliminary clinical evaluation

A new transdermal drug-delivery system that administers the synthetic opioid fentanyl through intact skin was evaluated for 24 hours postoperatively in eight patients who had undergone orthopedic surgery. Plasma samples were obtained over a 72-hour period for pharmacokinetic analysis in five patients. The patients were also evaluated intensively for adequacy of analgesia, frequency of nausea and sedation, and occurrence of ventilatory depression. A median lag time of 2.25 hours after application of the transdermal system was observed before the appearance of fentanyl in the blood. Median peak concentration and time to peak were 1.0 ng/ml and 22 hours, respectively. The apparent elimination of fentanyl after transdermal administration is prolonged relative to previously reported values. Absorption analysis indicates zero-order fentanyl administration, and in addition, suggests deposition of drug in an epidermal site, with the resultant prolonged absorption process giving the appearance of slow elimination. No significant toxicities were observed. Four patients required no additional analgesia. No consistent correlations among fentanyl concentration and any clinical values were observed. Transdermal administration of fentanyl appears to be a viable alternative to conventional routes of narcotic administration and warrants further study.     

Dose independent pharmacokinetics of mexiletine in healthy volunteers.

In 12 healthy volunteers who received orally 100, 200, 300, 400 and 600 mg mexiletine at weekly intervals, the maximum plasma concentration of mexiletine and AUC increased linearly with the dose of mexiletine. Between doses there were no significant differences in the values for clearance and volume of distribution of mexiletine but there were for plasma elimination half-life. These results indicate that the kinetics of mexiletine are linear.     

Intranasal loteprednol etabonate in healthy male subjects: pharmacokinetics and effects on endogenous cortisol

Loteprednol etabonate (LE) is a glucocorticoid soft drug that is currently in development for intranasal use. The main objectives of this study were to examine the pharmacokinetics and potential effects on systemic cortisol of two intranasal suspension formulations of LE and to compare these findings with placebo and fluticasone propionate (FP, Flonase) control treatments. In this randomized, double-blind (except for FP), parallel-group study (n = 8/group), all subjects received for 14 days once daily in the morning two puffs of the following nasal spray formulations into each nostril: LE 0.1% (400 microg/day), LE 0.2% (800 microg/day), FP 0.05% (200 microg/day), and placebo. Drug trough levels were determined on days 1, 5, 12, 13, and 14, and a full pharmacokinetic profile was established on day 14, and 24-hour serum cortisol profiles were assessed prior to treatment (i.e., at baseline) and after the last dose. All subjects completed the protocol without treatment-emergent adverse findings. All formulations were rapidly absorbed (t(max) less than 1 h). The rather short mean terminal half-lives of 2.2 +/- 1.5 hours and 1.8 +/- 1.0 hours for LE 400 microg and LE 800 microg, respectively, and 4.2 +/- 1.8 hours for the 200-microg FP treatment explained the lack of any accumulation. Mean peak concentrations (C(max)) were 139 +/- 57 pg/mL with LE 400 microg and 164 +/- 54 pg/mL with LE 800 microg and thus fairly independent from dose. The 200-microg FP treatment resulted in a C(max) of only 15.5 +/- 5.9 pg/mL. Mean measured AUC(0-t) values (193 +/- 87 pg/h/mL(-1), 300 +/- 183 pg/h/mL(-1), and 40 +/- 34 pg/h/mL(-1) for LE 400 microg, LE 800 microg, and FP 200 microg, respectively) showed high variability and suggested nonlinear pharmacokinetics for the LE formulations, indicative of a less complete systemic uptake of LE from the 0.2% concentration. None of the treatments (LE 400 microg, LE 800 microg, and FP 200 microg) showed evidence for serum cortisol suppression when compared with placebo, respectively. The uptake and systemic exposure appears less complete from the 0.2% LE concentration, which principally favors this formulation for further clinical development.     

Dose response of adrenocorticotropin and cortisol to the CCK-B agonist pentagastrin.

Cholecystokinin (CCK) is an abundant neurotransmitter in brain. Its functional significance in humans is incompletely understood, but it may modulate activity in the hypothalamic-pituitary-adrenal (HPA) axis. To explore this hypothesis, we examined the effects of varying doses (0 to 0.8 microgram/kg) of the CCK-B agonist pentagastrin on adrenocorticotropin (ACTH) and cortisol release in healthy human subjects. We also examined anxiety, heart rate (HR), and blood pressure (BP) responses. Pentagastrin induced large (up to 520% increase over baseline), significant and very rapid, dose-dependent elevations in ACTH and cortisol levels. Significant elevations in HR and BP were seen at all doses, without clear dose-response relationships. Anxious distress and symptom responses were also somewhat dose dependent; but hormonal responses were more robustly linked to pentagastrin dose than to these subjective measures. The HPA axis response to the CCK-B agonist pentagastrin may be a direct pharmacological effect. Further work is needed to determine the mechanisms and the physiological significance of CCK-mediated modulation of the human neuroendocrine stress axis.     

Dose dependent effect of diltiazem on the pharmacokinetics of nifedipine

The effect of diltiazem pretreatment on the pharmacokinetics of nifedipine were determined in six healthy male volunteers. Placebo or diltiazem (30 mg and 90 mg) was given orally three times daily for 3 days in a double-blind, Latin square method. On the fourth day, a 20-mg nifedipine was given orally 1 hour after the last dose of placebo or diltiazem. The mean elimination half-life of nifedipine prolonged significantly following diltiazem (2.54 hours on placebo vs 3.40 hours on 30 mg diltiazem and 3.47 on 90 mg diltiazem, both P less than .01). The mean AUC of nifedipine increased during diltiazem (1726.6 nmol X hr/ml on placebo vs 3838.0 on 30 mg diltiazem, and 5370.0 on 90 mg diltiazem, both P less than .05, 30 mg vs 90 mg, 0.1 less than P less than .05). The ratio of the AUC of primary metabolite (nitropyridine form) to the AUC of nifedipine was reduced by diltiazem pretreatment in a dose-dependent manner. ICG clearance was not influenced following diltiazem. These results indicate that diltiazem dose-dependently alters the pharmacokinetic profiles of nifedipine. The ICG clearance test showed that the liver blood flow did not decrease during diltiazem therapy, therefore, the reduction in the metabolic clearance of nifedipine might be caused by inhibiting effect of diltiazem on the activity of drug oxidizing enzymes.     

Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man

The pharmacokinetics after oral administration of 200, 600 or 1200 mg of N-acetylcysteine (NAC) were studied in 10 healthy subjects. Normalized maximal plasma concentration was significantly higher after a 600 mg dose than after a 200 mg dose. Bioavailability of NAC significantly increased with increasing dose. Time for maximal plasma concentration also increased with increasing dose. The observations can be explained by a capacity-limited presystemic elimination of NAC. In an extension of the study, 600 mg of NAC was given twice a day for 5 days and the plasma concentrations were followed after the morning dose on day 6. No differences in the pharmacokinetic parameters were observed in comparison with the single 600 mg dose. This indicates that the beneficial clinical effects observed after repeated dosing can not be ascribed to an accumulation of NAC in plasma.     

Dose optimisation of antibiotics in children: application of pharmacokinetics/pharmacodynamics in paediatrics

The judicious use of antibiotics to combat infections in children relies upon appropriate selection of an agent, dose and duration to maximise efficacy and to minimise toxicity. Critical to dose optimisation is an understanding of the pharmacokinetics and pharmacodynamics of available drugs. Optimal dosing strategies may take advantage of pharmacokinetic/pharmacodynamic (PK/PD) principles so that antibiotic dosing can be individualised to assure effective bacterial killing in patients who have altered pharmacokinetics or who have infections with less susceptible or resistant organisms. This review will outline the fundamentals of antimicrobial pharmacokinetics/pharmacodynamics through discussion of antibacterial agents most often used in children. We aim to highlight the importance of dose optimisation in paediatrics and describe non-conventional dosing strategies that can take advantage of PK/PD principles at the bedside.     

Dose ranging pharmacokinetics and brain distribution of norfloxacin using microdialysis in rats

The purpose of this study was to investigate the effect of dose on norfloxacin pharmacokinetics and distribution into the brain extracellular fluid (ECF), in freely moving rats. Unbound concentrations of norfloxacin in hippocampus were determined by microdialysis after an i.v. bolus dose of 12.5, 25, 50, 100, or 150 mg/kg in rats. In vivo recovery of norfloxacin was determined by retrodialysis by calibrator. Among three fluoroquinolones (enoxacin, pefloxacin, and ciprofloxacin) selected as potential calibrators, ciprofloxacin was selected as the best one. Maximum ECF brain norfloxacin concentrations are rapidly obtained but the ECFbrain/plasma areas under curves (AUC) ratios are low and independent of dose with a mean value of 8.2 +/- 5.8%. By contrast, norfloxacin systemic pharmacokinetics was nonlinear, with total plasma clearance decreasing significantly from 23.0 +/- 3.4 to 14.4 +/- 3.8 mL/min/kg when dose increased from 12.5 to 150 mg/kg.     

Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

Receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase (TAT) were evaluated in normal rats. A group of normal male Wistar rats were injected with 50 mg/kg methylprednisolone (MPL) intramuscularly at the nadir of their plasma corticosterone (CST) rhythm (early light cycle) and sacrificed at various time points up to 96 h post-treatment. Blood and livers were collected to measure plasma MPL, CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density, TAT mRNA, and TAT activity. The pharmacokinetics of MPL showed bi-exponential disposition with two first-order absorption components from the injection site and bioavailability was 21%. Plasma CST was reduced after MPL dosing, but resumed its daily circadian pattern within 36 h. Cytosolic receptor density was significantly suppressed (90%) and returned to baseline by 72 h resuming its biphasic pattern. Hepatic GR mRNA follows a circadian pattern which was disrupted by MPL and did not return during the study. MPL caused significant down-regulation (50%) in GR mRNA which was followed by a delayed rebound phase (60-70 h). Hepatic TAT mRNA and activity showed up-regulation as a consequence of MPL, and returned to their circadian baseline within 72 and 24 h of treatment. A mechanistic receptor/gene-mediated pharmacokinetic/pharmacodynamic model was able to satisfactorily describe the complex interplay of exogenous and endogenous corticosteroid effects on hepatic GR mRNA, cytosolic free GR, TAT mRNA, and TAT activity in normal rats.     

Dose proportionality and pharmacokinetics of dronedarone following intravenous and oral administration to rat

1. The aim of this study was to investigate the pharmacokinetic properties of dronedarone by using noncompartmental analysis and modeling approaches after intravenous and oral administration of dronedarone to rats.

2. Twenty-eight male Sprague-Dawley rats were randomly divided into four groups, and dronedarone was administered intravenously (1?mg/kg) and orally (5, 10 and 40?mg/kg) based on a parallel design. Blood samples were collected before and 0.083 (intravenous administration only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24?h after drug administration. The plasma concentration of dronedarone was determined by using LC-MS/MS.

3. The oral bioavailability of dronedarone was evaluated as approximately 16% in rats, similar to that in humans. The assessment of dose proportionality by using the power model showed that AUC_inf increased in a dose-proportional manner, whereas AUC_24h and C_max exhibited a lack of dose proportionality over the dose range between 5 and 40?mg/kg. The two-compartment model, with first-order absorption and elimination rate constants, was sufficient to explain the pharmacokinetics of dronedarone with biexponential decay.

4. These findings will help to understand the pharmacology of dronedarone to develop the new formulation and therapeutics optimization linked to pharmacokinetic/pharmacodynamic study.

     

Cefpiramide: antibacterial activity, pharmacokinetics, and clinical evaluation

We determined MIC values of cefpiramide (CPM) against clinical isolates from 100 patients who were subjected to total hysterectomy between April 1986 and March 1988. We also investigated the concentrations of CPM in uterine tissue and assessed the clinical efficacy of postoperative prophylaxis. 1. Against bacteria isolated from clinical materials the MIC80 values of CPM were as follows: Staphylococcus epidermidis 1.56 micrograms/ml, Enterococcus faecalis 25 micrograms/ml, and Escherichia coli 6.25 micrograms/ml. 2. Peak concentrations of CPM in various tissues and tissue/serum ratios of AUC were as follows: cervix uteri 35 micrograms/g (39.5%), perimetrium 43 micrograms/g (44.9%), endometrium 39 micrograms/g (51.6%), myometrium 28 micrograms/g (26.8%), oviduct 67 micrograms/g (41.9%), and ovary 27 micrograms/g (45.8%). In all tissues examined CPM concentrations were above 4 micrograms/g after 600 minutes. 3. Serum half-lives were T 1/2(alpha) = 13.2 minutes and T 1/2(beta) = 260.2 minutes. 4. The efficacy rate in postoperative prophylaxis was 97.9%. 5. No serious side effects were observed.