Richard J. Kowalsky

In vitro-in vivo correlation of hepatobiliary drug clearance in humans.

The biliary clearance (Clbiliary) of three compounds was estimated using sandwich‐cultured human hepatocytes (SCHH) and compared with Clbiliary values measured in vivo. Tc‐99m sestamibi (MIBI) Clbiliary was determined in seven healthy volunteers using an oroenteric catheter to aspirate duodenal secretions, and gamma scintigraphy to determine gallbladder contraction; this technique was used previously to determine Tc‐99m mebrofenin (MEB) and piperacillin (PIP) in vivo Clbiliary. In vitro Clbiliary of MEB, MIBI, and PIP was quantified in SCHH as the ratio of mass excreted into bile canaliculi and area under the blood concentration‐time curve (AUC) in medium. MIBI Clbiliary in vivo was 5.5±1.2 mL/min/kg (mean±SD). The rank order of Clbiliary predicted from SCHH corresponded well with the in vivo Clbiliary values in mL/min/kg for MEB (7.44 vs 16.1), MIBI (1.20 vs 5.51), and PIP (0.028 vs 0.032). In conclusion, the methods developed allowed for reproducible quantification of Clbiliary of drugs in healthy humans and prediction of Clbiliary from in vitro data.

Albumin Microspheres as a Drug Delivery System: Relation Among Turbidity Ratio, Degree of Cross-linking, and Drug Release

The degree of cross-linking of albumin microspheres, with and without drug, was assessed using turbidity measurements carried out in the presence of water and the protein denaturant guanidine hydrochloride (GuHCl) at a concentration that disrupted noncovalent bonds while having no effect on covalent bonds. The measurements allowed calculation of a turbidity ratio (TG/TW), expressed as the ratio of the turbidity of albumin microspheres in 6 M GuHCl (TG) divided by that in water (Tw). A linear relation existed between TG/TW and the (i) temperature at which the microspheres were prepared, (ii) concentration of the cross-linking agent glutaraldehyde, and (iii) time of exposure to a second cross-linking agent, formaldehyde vapor, three conditions that increase the degree of cross-linking. The turbidity ratio also increased as the concentration of the albumin solution used to prepare the microspheres increased from 25 to 50%. Drug release from the microspheres consisted of an initial, rapid, burst followed by a second, slower, phase. The rates in both release phases were inversely related to the turbidity ratio, suggesting that this parameter has utility as an indicator of the degree of cross-linking in albumin microspheres.

A novel method for the determination of biliary clearance in humans

Biliary excretion is an important route of elimination and the biliary tract is a potential site of toxicity for many drugs and xenobiotics. Quantification of biliary excretion in healthy human volunteers is logistically challenging and is rarely defined during drug development. The current study uses a novel oroenteric tube coupled with a specialized clinical protocol to examine the pharmacokinetics of99mTechnetium (Tc-99m) mebrofenin, a compound that undergoes rapid hepatic uptake and extensive biliary excretion. A custommade multilumen oroenteric tube was positioned in the duodenum of healthy human volunteers. Subjects were positioned under a gamma camera and 2.5 mCi of Tc-99m mebrofenin was administered intravenously. Duodenal aspirates, blood samples, and urine were collected periodically for 3 hours. Two hours after Tc-99m mebrofenin administration, the gallbladder was contracted with an intravenous infusion of cholecystokinin-8. Gamma scintigraphy was used to determine the gallbladder ejection fraction in each subject. Total systemic clearance of Tc-99m mebrofenin approximated liver blood flow (Cltotal 17.3±1.7 mL/min/kg), and 35% to 84% of the Tc-99m mebrofenin dose was recovered in bile. However, when the data were corrected for the gallbladder ejection fraction, 71% to 92% of theexcreted Tc-99m mebrofenin dose was recovered. This novel croenteric tube and clinical protocol provide a useful method to quantify biliary excretion of xenobiotics in healthy human volunteers.

A Basic Overview of Radiopharmaceuticals and Their Relationship to Nuclear Pharmacy Practice

Radiopharmaceuticals are radioactive drugs used to diagnose and treat disease with radiation. Following patient administration of a radiopharmaceutical, γ-camera images are made of its localization and distribution within specific organs. The images obtained provide information that the nuclear medicine physician can use to make a diagnosis. Dynamic imaging studies provide functional information through measurement of the rates of accumulation and removal of the radiopharmaceutical by the organ. Static images provide morphologic information regarding organ size, shape, and position, the presence of space-occupying lesions, and relative function. In general, nuclear medicine studies can be used to determine whether a disease is present, to evaluate the progress of disease following drug therapy, and to evaluate drug-induced toxicity. Additionally, radiopharmaceuticals can be used to arrest certain types of illness through the localized in vivo destruction of diseased tissue with radiation. Nuclear pharmacists prepare radiopharmaceuticals, perform quality control tests to assure their identity, quantity, and purity before patient administration, and provide professional advice on the safe and efficacious use of these agents.

Radioiodinated bleomycin: Stoichiometry of iodination and structural characterization by 1H-nuclear magnetic resonance

Bleomycin was iodinated by reaction with iodine monochloride (ICl). A direct relationship was found to exist between the average number of iodine atoms bound per molecule of bleomycin and the ICl: bleomycin molar ratio. Characterization by 1H-NMR analysis denoted that mono, di-, tri- and tetraiodobleomycin are formed when the reacting molar ratios, respectively, are 2:1, 4:1, 6.8:1 and 8.5:1 or greater. The sites of iodination of the bleomycin molecule have been identified to be the imidazole ring which iodinates first, followed by the bithiazole ring system which iodinates last.