Pharmacokinetics and Temperature

Ballard, Berton E.

doi:10.1002/jps.2600630903

Cited by 70 publications

(22 citation statements)

References 127 publications

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“…This may reflect the differences in the absorption and disposition kinetics of ketoconazole among the subjects. The greater intersubject variation observed after administration of the tablet formulation (Table 2) may have been due to the fact that the dissolution, and therefore the absorption, of ketoconazole requires a low gastric pH (pH <3) (2) and the fasting gastric pH values vary among subjects (1).…”

Section: Materials Amd Methodsmentioning

confidence: 99%

Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers

Huang¹,

Colaizzi²,

Bierman³

et al. 1986

Antimicrob Agents Chemother

111

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Ketoconazole is an orally effective, broad-spectrum, systemic antifungal agent. The pharmacokinetics and bioavailability of ketoconazole given as a 200-mg single dose in a tablet, suspension, or solution were studied in 24 fasting healthy males by using a crossover design. Levels of ketoconazole in plasma were determined for up to 48 h by a sensitive reverse-phase high-performance liquid chromatography method. The absorption of ketoconazole was rapid, with mean maximum concentrations of the drug in plasma of 4.2, 5.0, and 6.2 ,g/ml attained at 1.7, 1.2, and 1.0 h, respectively, after administration of the tablet, suspension, and solution, respectively. The mean distribution and elimination half-life values were 1.5 to 1.7 and 7.5 to 7.9 h, respectively. The mean oral clearance of the solution dose was 209 (+82.9 [standard deviation]) ml/min, and the mean apparent volume of distribution was 88.31 (±68.72) liters. The relative bioavailabilities for the tablet and suspension were 81.2 (±33.5) and 89.0 (±23.1)%, respectively, of that of the solution. The data indicated the bioequivalence of the tablet to the suspension and of the suspension to the solution. Dose proportionality of ketoconazole was also studied in 12 volunteers after they received solution doses of 200, 400, and 800 mg. Linear correlations between the dose and the maximum concentration of the drug in plasma, the time to the maximum concentration, and the area under the concentration-time curve were observed. However, the increase in the area under the curve was more than proportional to the dose given. The levels in plasma seemed to decay at a lower rate after 400-and 800-mg doses. The mean oral clearance decreased from 244.9 to 123.6 and 80.0 ml/min, respectively, as the dose increased from 200 to 400 and 800 mg. The apparent dose-dependent kinetics may have been due to the presystemic elimination and capacity-limited hepatic metabolism which become saturated at higher doses.Ketoconazole is a synthetic imidazole-dioxolane derivative with a broad spectrum of antifungal activity. Although its spectrum of activity is similar to those of other imidazole derivatives, e.g., miconazole, econazole, and clotrimazole, ketoconazole has the advantage of being effective when administered orally. Its therapeutic efficacy was reviewed recently (7). After a 200-mg tablet dose to healthy subjects, peak ketoconazole concentrations in plasma (Cmax) of 3 to 4.5 ,ug/ml were reached within 1 to 2 h and the therapeutic activity was maintained for several hours after administration of the drug (8). The recommended dosage for ketoconazole is 200 mg daily. In serious infections, higher doses may be required. Ketoconazole is available as a 200-mg tablet (10).The objectives of this study were (i) to determine the bioavailabilities of the ketoconazole tablet and an experimental suspension formulation relative to a reference aqueous solution and (ii) to evaluate in healthy, male volunteers the dose proportionality of ketoconazole in doses ranging from 200 to 800 mg. MATERIALS AM...

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Section: Materials Amd Methodsmentioning

confidence: 99%

Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers

Huang¹,

Colaizzi²,

Bierman³

et al. 1986

Antimicrob Agents Chemother

111

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“…All of these above studies except one were performed using ultrafiltration which tends to give higher values for degree of binding, possibly relating to nonspecific binding to the membrane (Chignell, 1977). They were also performed at room temperature rather than at 37C and this will increase the percentage binding of many drugs (Ballard, 1974). Finally the possible effect of pH will be discussed presently.…”

Section: Normal Subjectsmentioning

confidence: 99%

Determinants of the plasma protein binding of theophylline in health.

Buss¹,

Leopold²,

Smith³

et al. 1983

Brit J Clinical Pharma

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1 The plasma protein binding of theophylline was determined after addition of ['4C]-theophylline (15 ,g/ml) to plasma from 24 healthy drug-free volunteers and equilibrium dialysis for 2 h at 37°C. 2 The percentage of drug unbound was 60.0% 2.2% (s.d.) with very little variation between individuals. The binding ratio of theophylline was not significantly related to the plasma albumin or a,-acid glycoprotein (AAG) concentrations but was significantly, although weakly, negatively related to the logarithm of the non-esterified fatty acid concentration (NEFA) (r = 0.443, P < 0.05). 3 Intravenous administration of heparin (1000 units) caused a significant rise in plasma NEFA concentration and in the percentage of drug unbound in plasma after equilibrium dialysis. 4 In human serum albumin solutions, the binding ratio of theophylline was significantly related to the albumin concentration and at the albumin concentration seen in the 24 normal subjects, the percentage of drug unbound was almost identical. Addition of AAG in physiological concentrations did not enhance theophylline binding but oleic acid, and to a lesser extent palmitic acid, reduced binding significantly. 5 The percentage of theophylline unbound in plasma varied markedly with pH so that at pH7 the percentage unbound was 52% greater than at pH 8. There was no evidence of concentration dependence of binding up to 140 ,ug/ml theophylline.6 Theophylline appears to bind almost exclusively to albumin and its plasma protein binding varies little in healthy subjects, showing no concentration-dependence over the therapeutic range of concentrations. The binding is affected by pH and by NEFA concentration, however, and these factors may be of greater importance in disease states. Caution should be employed in the use of heparin in studies of plasma protein binding of theophylline.

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“…The effect of variation in temperature on drug pharmacokinetics had not been widely studied when the subject was reviewed by Ballard in 1974, with the conclusion that both hyperthermia and hypothermia may in some instances influence the pharmacokinetic behaviour of a drug. For example, the rate of binding of 32p Thiotepa to perfused hind limbs of dogs was shown to be higher at tissue tempera-tures of 37-2-38-90C than at 23-9-26410C (Rochlin et al, 1961).…”

mentioning

confidence: 99%

Effects of local hyperthermia on the pharmacokinetics of misonidazole in the anaesthetized mouse

Honess¹,

Workman²,

Morgan³

et al. 1980

Br J Cancer

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Summary.-The effects of sodium pentobarbitone anaesthesia, the presence of a tumour, and local hyperthermia to a tumour-bearing leg, on the pharmacokinetics of MISO in the mouse are reported. Analysis of MISO and its metabolite Ro 05-9963 was by high-performance liquid chromatography. The plasma kinetics of MISO were largely unaffected by any of these treatments, but hyperthermia substantially reduced tumour concentrations of the drug.The effects of tumour site and size on unheated-tumour drug concentrations were also studied, and an increase in tumour size was shown to decrease tumour MISO levels, but to different degrees according to whether implanted in the leg or flank.Uniformity of MISO distribution throughout heated and unheated tumours was examined, and levels were found to be constant within tumours. The presence of a temperature detector in heated tumours did not affect their drug concentration.

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Pharmacokinetics and Temperature

Cited by 70 publications

References 127 publications

Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers

Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers

Determinants of the plasma protein binding of theophylline in health.

Effects of local hyperthermia on the pharmacokinetics of misonidazole in the anaesthetized mouse

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