Drug lipophilicity and release pattern of some β-blocking agents after intra-adipose injection in pigs

Abstract

Release rates from intramuscular and intra-adipose injection sites have turned out to be dependent upon several factors including injection depth. Little is known about the interaction between drug lipophilicity and transport rate of drugs through adipose and muscle tissue. The principal objective of the present study was to determine to what extent drug lipophilicity affects release and release rate from adipose tissue. Nine pigs were given intravenous (0.1 mg/kg), intramuscular (0.2 mg/kg) and intra-adipose (0.2 mg/kg) injections of propranolol, alprenolol, carazolol, metoprolol and atenolol. The fraction not-absorbed vs time plots after intramuscular and intra-adipose injection showed a biphasic decline for all model compounds with the exception of atenolol being the most hydrophilic drug. This biphasic decline indicates that two different mechanisms may be involved in drug release. Initial release rates after intra-adipose injection were negatively correlated (Kendall's rank order test) with fat-buffer partition constants. The second release phase was best characterized by the extent of 24 h release. The amounts (mean ± S.D.) released after 24 h for propranolol, alprenolol, carazolol, metoprolol and atenolol are 42 ± 15, 38 ± 9, 45 ± 18, 48 ± 12 and 99 ± 12% following intra-adipos injection and 57 ± 8, 36 ± 18, 38 ± 15, 55 ± 14 and 104 ± 14% after intramuscular injection, respectively. Incomplete release at 24 h can be explained by the sunk solvent drag after absorption of the solvent is complete. Octanol-buffer partition and pig-fat-buffer distribution constants turned out to be positively correlated.