THE SITE OF ABSORPTION IN THE SMALL INTESTINE DETERMINES DILTIAZEM BIOAVAILABILITY IN THE RABBIT

ABSTRACT Purpose. Since the ability of the small intestine to biotransform a drug may decrease in distal segments of the intestine, this study aimed to assess whether the site of administration in the small intestine could affect the systemic bioavailability of diltiazem and its two active metabolites, N-desmethyldiltiazem (MA) and desacetyldiltiazem (M1). Methods. Five mg/kg of diltiazem were administered into the lumen of the proximal (0-30 cm, n=9) or the distal (150-180 cm) small intestine (n=7) of anesthetized New Zealand rabbits. Blood samples were drawn from the femoral artery for 6 hours, and diltiazem, MA and M1 were assayed by HPLC. Results. The area under the curve (AUC 0→∞ ) of diltiazem administered into the distal small intestine was larger than that estimated when diltiazem was given in the proximal segment (14.20 ± 2.82 vs 8.14 ± 0.88 µg.min/ml, p<0.05), due to a lower diltiazem oral clearance (440 ± 78 vs 660 ± 55 ml/min/kg, p<0.05). The AUC 0→360 of MA was not affected by the site of diltiazem administration, but the AUC 0→360 of M1 was increased when diltiazem was administered in the distal segment of the small intestine. Since the molar sum of diltiazem and its active metabolites was 48% greater following administration into the distal segment as compared to the 0-30 cm segment of the small intestine, absorption of diltiazem in distal segments of the intestine may enhance its pharmacological response. Conclusions. The site of absorption into the intestine modulates the bioavailability of diltiazem and its two active metabolites

FIRST-PASS METABOLISM OF LIDOCAINE IN THE ANESTHETIZED RABBIT Contribution of the Small Intestine

ABSTRACT: it is assumed that, In vlvo, the liver is the organ responsible for th

PRESYSTEMIC ELIMINATION OF MORPHINE IN ANESTHETIZED RABBITS Contribution of the Intestine, Liver, and Lungs

ABSTRACT: To assess the role of the intestine and the lung in the first-pass uptake of morphine relative to that of the liver, five groups of 6-

Tetrodotoxin for Moderate to Severe Cancer-Related Pain: A Multicentre, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Trial

Objective. This study evaluated subcutaneous injections of tetrodotoxin (TTX) for the treatment of moderate to severe, inadequately controlled cancer-related pain. Methods. Eligible patients were randomized to receive TTX (30?µg) or placebo subcutaneously twice daily for four consecutive days. Efficacy was assessed using pain and composite endpoints (including pain and quality of life measures), and safety was evaluated using standard measures. Results. 165 patients were enrolled at 19 sites in Canada, Australia, and New Zealand, with 149 patients in the primary analysis “intent-to-treat” population. The primary analysis supports a clinical benefit of TTX over placebo based on the pain endpoint alone with a clinically significant estimated effect size of 16.2% (). The value was nominally statistically significant after prespecified (Bonferroni Holm) adjustment for the two primary endpoints but not at the prespecified two-sided 5% level. The mean duration of analgesic response was 56.7 days (TTX) and 9.9 days (placebo). Most common adverse events were nausea, dizziness, and oral numbness or tingling and were generally mild to moderate and transient. Conclusions. Although underpowered, this study demonstrates a clinically important analgesic signal. TTX may provide clinically meaningful analgesia for patients who have persistent moderate to severe cancer pain despite best analgesic care. This clinical study is registered with ClinicalTrials.gov (NCT00725114).Peer Reviewe