Food, Acid Supplementation and Drug Absorption - a Complicated Gastric Mix: a Randomized Control Trial.

PURPOSE:The purpose of this study was to determine the impact of food on gastric pH and the ability of over the counter betaine hydrochloride (BHCl) acid to reacidify gastric pH after food-induced elevations in gastric pH. METHODS:This open-label cross over clinical study (NCT02758015) included 9 subjects who were randomly assigned to one of 16 possible, 4-period cross-over sequences to determine the impact and relationship of food and gastric pH with acid supplementation. Subjects were administered various doses (1500 mg, 3000 mg and 4500 mg) of betaine hydrochloride (BHCl) to determine the ability of acid supplementation to reacidify gastric pH after the elevation of gastric pH caused by the ingestion of food. RESULTS:Following the administration of food and the resulting elevation in gastric pH, time to return to baseline gastric pH levels without acid supplementation was 49.7 ± 14.0 min. Administering 4500 mg of BHCl acid in capsules was able to reacidify gastric pH levels back to baseline following the administration of food in approximately 17.3 ± 5.9 min. AUCpH of each treatment were similar and not statistically different. Mean max pH following the administration of food was 3.20 ± 0.55. CONCLUSION:The ability of food to elevate and maintain gastric pH levels in the presence of acid supplementation was made evident throughout the study. A 4500 mg dose of BHCl was required to reacidify gastric pH after the administration of food. This study details the difficulty faced by clinicians in dosing a poorly soluble, weakly basic drug to patients receiving acid reducing agents where administration with food is recommended to avoid gastric side effects. TRIAL REGISTRATION:https://clinicaltrials.gov/ct2/show/NCT02758015

Biotransformation of furosemide in kidney transplant patients

The metabolic fate of furosemide was studied in kidney transplant patients after oral and intravenous administration of the diuretic at therapeutic doses. Serial urine samples were collected over a 24 h period and furosemide was analyzed by a specific high performance liquid chromatographic method using fluorescence detection. We found no evidence of the putative furosemide metabolite, 2-amino-4-chloro-5-sulfamoylanthranilic acid (CSA), in any of the samples analyzed. The amount of furosemide excreted as the glucuronide metabolite accounted for 8% of the available dose, whether administered orally or by intravenous infusion. In addition, the significant positive correlation observed between the percent of the available dose excreted as furosemide glucuronide and the renal clearance of furosemide ( r =0.581, p <0.02) suggests that the glucuronidation process for furosemide may be occurring in the kidney. Furosemide and its glucuronide metabolite accounted for only 45% of the intravenous dose recovered in the urine. Biliary excretion of unchanged furosemide and/or furosemide glucuronide into the feces probably accounts for the remainder of the dose not recovered.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46639/1/228_2004_Article_BF00607088.pd

Furosemide kinetics and dynamics after kidney transplant

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110005/1/cptclpt1981134.pd

Membrane transporters in drug development

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling. © 2010 Macmillan Publishers Limited

Role of intestinal P‐glycoprotein ( mdr1 ) in interpatient variation in the oral bioavailability of cyclosporine

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110064/1/cptclpt1997116.pd