James John Benedict

Clodronate kinetics and bioavailability

Carbon 13–labeled clodronate disodium was given to healthy adult men by intravenous infusion and orally in a crossover design. Serum and urine levels were determined as a function of time by isotope‐ratio mass spectrometry. Clodronate disodium (Cl2MDP) is primarily excreted unchanged by the kidney; more than 80% of the intravenous dose was recovered within 48 hr. The serum concentration‐time curve over the first 8 hr after intravenous dosing appears biexponential with the disposition phase having a harmonic mean half‐life (t½) of 2 hr. The mean serum clearance was found to be 1.4 ml min−l kg−l and the apparent volume of distribution was approximately 25% of body weight. Simulations and computer fitting of the cumulative urinary excretion and urinary excretion rates based on the biexponential serum decay curve demonstrated the presence of a slow disposition component with a t½ of 12.8 hr. Thus, the disposition kinetics of Cl2MDP appear to be triexponential, although the slowest component is not of major significance after a single dose and could not be verified because of a lack of serum data after 8 hr. Cl2MDP is poorly absorbed with an absolute bioavailability of only 1% to 2%.

31P NMR as a spectroscopic monitor of the spontaneous precipitation of calcium phosphates

SummaryHigh-resolution31P NMR spectroscopy is shown to be a potentially valuable new method for monitoring the spontaneous precipitation of calcium phosphates from metastable supersaturated solutions. An apparatus capable of pH-statting the sample in a spinning 20 mm NMR sample tube is briefly described. The spontaneous precipitation of dicalcium phosphate dihydrate, CaHPO4· 2H2O, pH-statted at pH 5, is characterized by a base-uptake curve which follows the decrease in the intensity of the solution31P resonance. The precipitation of amorphous calcium phosphate at neutral pH, which exhibited an induction period of ∼ 10 min, was also studied. No evidence of NMR peaks from transient clusters or the initial colloidal solid phase has been seen.

pH control and rapid mixing in spinning NMR samples

Abstract An apparatus is described which permits the acquisition of NMR spectra from spinning 20-mm sample tubes while: (1) constantly monitoring the pH; (2) adding reagents to maintain constant pH (pH-statting); (3) efficiently mixing the added reagent. The apparatus was built to study the spontaneous precipitation of calcium phosphates from supersaturated solutions using 31 P NMR. Other applications include the rapid determination of NMR titration curves, and the minimization of temperature gradients in large sample tubes. The apparatus was used to measure the 31 P chemical shift titration of dilute phosphoric acid, which yielded accurate shifts for the three species of protonated orthophosphate ion. The bulk magnetic susceptibility of 85% H 3 PO 4 relative to a dilute aqueous sample was also measured, and is shown to contribute significantly to chemical shift measurements.