控释胶囊剂中Dexatrim（盐酸苯丙醇胺）的生物利用度及心血管安全性

Bioavailability and cardiovascular safety of Dexatrim (phenylpropanolamine hydrochloride) from a controlled-release caplet.

作者信息

Shargel L, Silverman H I, Cohen P, Brisson J, Dennis S

机构信息

Massachusetts College of Pharmacy and Allied Health Sciences, Boston 02115.

出版信息

Biopharm Drug Dispos. 1990 Oct;11(7):569-83. doi: 10.1002/bdd.2510110703.

DOI:10.1002/bdd.2510110703

PMID:2265237

Abstract

The bioavailability and pharmacokinetics of phenylpropanolamine hydrochloride (PPA HCl) from a Dexatrim controlled-release (CR) caplet and solution was studied. Each subject (n = 12) received either a 75 mg PPA HCl CR caplet once daily or a 25 mg PPA HCl solution given three times a day. All subjects received the medication for 4 consecutive days. On Day 1, the mean +/- SEM, AUC, tmax, and Cmax values were 1651 +/- 127 ng x h ml-1, 4.5 +/- 0.26 h and 143 +/- 13.5 ng ml-1, respectively, for the CR caplet and 1716 +/- 90.3 ng x h ml-1, 1.25 +/- 0.08 h and 126 +/- 5.8 ng ml-1 for the solution, respectively. At steady state (Day 4), the mean +/- SEM, AUC, tmax, and Cmax values were 1832 +/- 101 ng x h ml-1, 4.17 +/- 0.17 h and 151 +/- 6.5 ng ml-1, respectively, for the CR caplet and 2014 +/- 116 ng x h ml-1, 1.33 +/- 0.09 h and 143 +/- 8.7 ng ml-1, respectively, for the solution. The data from Day 1 were fitted to an oral one compartment model with a first order absorption rate constant, kA, first order elimination rate constant, k and lag time. The mean +/- SEM, kA, elimination half-life and lag time for PPA HCl from the CR caplet were 0.488 +/- 0.182 ng h ml-1, 5.84 +/- 1.66 h and 0.394 +/- 0.224 h, respectively. The mean +/- SEM, kA, elimination half-life and lag time for PPA HCl from the solution were 2.87 +/- 1.51 ng x h ml-1, 3.73 +/- 1.21 h, and 0.325 +/- 0.101 h, respectively. The smaller apparent kA and longer elimination half-life for PPA HCl from the CR caplet is due to the slow release of PPA HCl, thereby slowing its absorption producing sustained plasma drug concentrations. Blood pressures (supine and sitting) and heart rates measured at the time of blood sampling after the administration of the PPA HCl dosage forms demonstrated no clinically significant relationship between cardiovascular response and PPA HCl plasma concentration. These data demonstrate the bioavailability and pharmacokinetics of PPA HCl from a CR caplet and an immediate release solution.

摘要

研究了盐酸苯丙醇胺（PPA HCl）从Dexatrim控释（CR）胶囊和溶液中的生物利用度及药代动力学。每位受试者（n = 12）每天服用一次75 mg PPA HCl CR胶囊或每天服用三次25 mg PPA HCl溶液。所有受试者连续服药4天。第1天，CR胶囊的平均±标准误、AUC、tmax和Cmax值分别为1651±127 ng·h·ml⁻¹、4.5±0.26 h和143±13.5 ng·ml⁻¹，溶液的分别为1716±90.3 ng·h·ml⁻¹、1.25±0.08 h和126±5.8 ng·ml⁻¹。在稳态（第4天）时，CR胶囊的平均±标准误、AUC、tmax和Cmax值分别为1832±101 ng·h·ml⁻¹、4.17±0.17 h和151±6.5 ng·ml⁻¹，溶液的分别为2014±116 ng·h·ml⁻¹、1.33±0.09 h和143±8.7 ng·ml⁻¹。第1天的数据拟合为具有一级吸收速率常数kA、一级消除速率常数k和滞后时间的口服单室模型。PPA HCl从CR胶囊中的平均±标准误、kA、消除半衰期和滞后时间分别为0.488±0.182 ng·h·ml⁻¹、5.84±1.66 h和0.394±0.224 h。PPA HCl从溶液中的平均±标准误、kA、消除半衰期和滞后时间分别为2.87±1.51 ng·h·ml⁻¹、3.73±1.21 h和0.325±0.101 h。CR胶囊中PPA HCl的表观kA较小且消除半衰期较长是由于PPA HCl的缓慢释放，从而减慢了其吸收，产生持续的血浆药物浓度。在给予PPA HCl剂型后采血时测量的血压（仰卧位和坐位）和心率表明，心血管反应与PPA HCl血浆浓度之间无临床显著相关性。这些数据证明了PPA HCl从CR胶囊和速释溶液中的生物利用度及药代动力学。