Application of dual radiotelemetric technique in studying drug-drug interaction between diclofenac sodium and ranitidine HCl in volunteers.

Drug-drug interaction between a commercial diclofenac sodium enteric-coated tablet (Voltaren; V) and a ranitidine HCl tablet (Zantac; Z) was evaluated using a dual radiotelemetric technique according to a randomized three-way Latin-Square crossover design balanced for carryover effects. V and Z were given either alone or in combination (Treatment V, Z, V/Z), with a 14-day washout period between treatments. Eighteen fasted subjects swallowed a tethered. Heidelberg pH capsule to provide continuous gastric pH. Then the assigned treatment drug and another Heidelberg pH capsule were given simultaneously. The free pH capsule provided information regarding gastric residence time (GRT). Serial blood samples were obtained for up to 12 hr after dosing and drug levels were determined by validated HPLC methods. Treatment effects on AUC, Cmax, Tmax, Tlag, Tmax-Tlag, and T1/2 were not significant except Cmax, which differed slightly for both V and Z when given in combination as compared to alone. Gastric residence times were 46, 33, and 51 min for Treatments V, Z, and V/Z, respectively. Gastric exposure of the enteric-coated tablet of diclofenac was estimated by pH values obtained from the tethered capsule. Median pH values at 3 and 15 min prior to gastric emptying were 3.8 and 4.9 for the combination treatment versus 2.1 and 2.7 for diclofenac alone. The results of this study indicated that there was minimal drug-drug interaction between diclofenac and ranitidine. The gastric pH range resulting from this study did not influence the oral absorption of enteric-coated diclofenac.

Application of radiotelemetric technique in evaluating diclofenac sodium absorption after oral administration of various dosage forms in healthy volunteers.

A radiotelemetric technique with the Heidelberg capsule (HC) was used to improve the quality of data generated in a bioavailability study involving an enteric-coated (EC) formulation. Further, changes in plasma levels of the drug from other dosage forms were related to changes in pH environment as determined by the HC. Eight healthy male subjects received the following treatments, 15 min after a light breakfast, according to a randomized, four-way crossover design: (A) HC and 75 mg of a diclofenac sodium aqueous buffered solution: (B) HC and one 75-mg Voltaren EC tablet; (C) HC and one 100-mg Voltaren slow-release (SR) tablet; and (D) HC alone. Each treatment was separated by a 1-week washout period. Two additional subjects subsequently received Treatment B only. Multiple peaks were observed in the drug plasma level-time profiles for the buffered aqueous solution which, in all cases, occurred before gastric emptying of the HC. The multiple peaks were not observed for the Voltaren SR tablet, but a variable absorption lag time occurred which coincided with the gastric residence time of the SR tablet. For the EC tablet the variability of individual plasma level-time profiles was drastically reduced when the time after dosing was adjusted to coincide with gastric emptying of the HC. Finally, the lag time between gastric emptying of the EC tablet and the onset of drug absorption was consistently at 1 hr for all subjects. This lag time was longer than the in vitro disintegration or dissolution times measured under USP conditions.