Pharmacokinetics and pharmacodynamics of ranitidine in renal impairment

Abstract

Objective: The pharmacodynamics and pharmacokinetics of ranitidine were examined in subjects with varying degrees of renal function to determine the effect of this condition on acid-antisecretory activity.

Methods: Subjects with creatinine clearances (C_Cr) ranging from 0 to 213 ml · min⁻¹ received single 50-mg and 25-mg i.v. doses of ranitidine. This was followed by determination of serum and urine ranitidine concentrations, and continuous gastric pH monitoring for 24 h.

Results: Serum ranitidine concentrations were described by a two-compartment model linked to a sigmoidal E_max model describing gastric pH. Ranitidine renal clearance, ranging from 0 to 1003 ml · min⁻¹, correlated with C_PAH (r ² = 0.707), while non-renal clearance was unaltered. Steady-state volume of distribution decreased by half in severe renal impairment. No changes in the effective concentration at half-maximal response (EC₅₀), maximal response (E_max), or basal response (E₀) were observed. Thus, renal elimination of ranitidine declined in parallel with renal function, while sensitivity to the pharmacologic effect (gastric pH elevation) was unaltered. Ranitidine was well tolerated in these renally impaired subjects.

Conclusion: These data indicate that the current recommendation for renal impairment dose reduction (by two-thirds when C_Cr<50 ml · min⁻¹) might result in under-treating moderately impaired patients, and suggests a less conservative dose reduction (by half when C_Cr<10 ml · min⁻¹) to avoid therapeutic failure while remaining within the wide margin of safety for this drug.