Low Intersubject Variability Research Articles

Sustained Absorption does not Necessarily Reduce the Systemic Availability of Propranolol

The in vitro dissolution and in vivo pharmacokinetics of two marketed long-acting propranolol formulations, Duranol (D) and Inderal LA (LA) were examined. Dissolution rates were obtained using the USP rotating basket method, while the relative bioavailabilities of the products were evaluated in normal volunteers under single-dose (6 subjects) and steady-state (11 subjects) conditions in two separate crossover studies. Both LA and D demonstrated pH-independent dissolution profiles with T50 values of 4 and 6 hours, respectively. While the dissolution profile for D was sigmoidal and complete in 12 hours, data for LA suggested a log-linear profile and indicated only 85% dissolution at 12 hours. In pharmacokinetic studies the tmax was achieved in 7 to 8 hours for both products; however, Cmax values for D vs LA were 80.4 vs 49.9 ng/ml (p < 0.05) after a single dose and 76.6 vs 52.6 ng/ml (p < 0.01) at steady-state drug administration. The bioavailability of D was 55% and 44% greater than that of LA during single-dose and steady-state studies, respectively. Intersubject variability was lower for D than for LA during both studies. The data indicate that sustained absorption does not necessarily reduce the systemic availability of propranolol, and suggest that formulation-related factors may contribute to the low bioavailability of LA. The superior bioavailability and lower intersubject variability achieved with D compared to LA suggest that D should be at least as effective as LA in the treatment of cardiovascular disorders.

Prednisolone clearance: a possible determinant for glucocorticoid efficacy in patients with oral vesiculo-erosive diseases.

The pharmacokinetics of prednisolone were determined in 12 patients with oral vesiculo-erosive diseases. The bioavailability of prednisone in these patients exhibited a low intersubject variability, while the metabolic clearance rate of total and of unbound prednisolone varied considerably from patient to patient.

Book reviews

The cannabinoid type-1 (CB1) receptor is one of the most abundant G-coupled protein receptors in the human body and is responsible for signal transduction of both endogenous and exogenous cannabinoids. The endocannabinoid system is strongly implicated in regulation of homeostasis and several neuropsychiatric disorders, obesity, and associated comorbidities, such as dyslipidemia and metabolic syndrome. We have used whole-body PET/CT to characterize the biodistribution and dosimetry of a novel high-affinity, subtype-selective radioligand, ¹⁸F-MK-9470, in healthy male and female subjects. <b>Methods:</b> Eight nonobese subjects (5 men, 3 women; age, 22–54 y) underwent serial whole-body PET/CT for 6 h after a bolus injection of 251 ± 25 MBq ¹⁸F-MK-9470 (<i>N</i>-[2-(3-cyano-phenyl)-3-(4-(2-¹⁸F-fluorethoxy)phenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylproponamide). Source organs were delineated 3-dimensionally using the combined morphologic and functional data. Residence times were derived from time–activity profiles using both the trapezoid rule and curve fitting. Individual organ doses and effective doses were determined using the OLINDA software package, with different approaches for gastrointestinal and urinary excretion modeling. <b>Results:</b>¹⁸F-MK-9470 is taken up slowly in the brain, reaching a plateau at approximately 90–120 min after bolus injection and is excreted predominantly through the hepatobiliary system. The gallbladder, upper large intestine, small intestine, and liver are the organs with the highest absorbed dose (average: 159, 98, 87, and 86 μGy/MBq, respectively). The mean effective dose (ED) was 22.8 ± 4.3 μSv/MBq, indicating relatively low intersubject variability and a mean value in the range of many commercially available ¹⁸F-labeled radiopharmaceuticals. Brain uptake was relatively high compared with that of existing central nervous system ligands for other receptors, between 3.2% and 4.9% of the injected dose. <b>Conclusion:</b> The estimated radiation burden of ¹⁸F-MK-9470 for PET CB1 receptor imaging shows relatively low variability between subjects and has an acceptable ED, which allows multiple serial cerebral scans of good image quality, while remaining within the risk category class II-b defined by the World Health Organization and the International Commission for Radiation Protection for a standard injected activity (185–370 MBq).