Physicochemical characterisation of drug-cyclodextrin complexation: impact on intravenous drug pharmacokinetics

2017-02-23T23:05:03Z (GMT) by Leong, Nathania Jing-Ai
Modified cyclodextrins used in intravenous drug formulation have often been regarded as inert carriers. This expectation has occasionally been challenged with few examples where the presence of the cyclodextrin results in significant changes to drug distribution. Such changes have been further exemplified by clear alterations in pharmacodynamics, toxicity profiles and plasma and urinary pharmacokinetics. These rare occurrences have been attributed to unusually strong association between drug (D) and cyclodextrin (CD). The studies presented in this thesis were designed to gain further understanding of the implications and relevance of in vitro binding constants on in vivo situations. The main areas explored were the impact of intravenous cyclodextrin formulations on the systemic and renal disposition of various drugs. Previous expectations have been that altered pharmacokinetics arise from unusually strong D-CD interactions. As literature precedents have indicated a particularly good fit between adamantane rings and β-CD, the pharmacokinetics of a series of structurally similar adamantane analogues was assessed. In vitro partitioning and in vivo pharmacokinetic studies demonstrated that equilibrium binding constant studies between D and CD cannot be used to predict the potential for systemic CD to influence the plasma pharmacokinetics of rimantadine (RIM), a compound with a “typical" binding constant (K = 2.1 x 10⁴ Mˉ¹). Rather, the altered pharmacokinetics appeared to be related to a series of competing equilibria between red blood cell (and tissue), protein and SBE7-β-CD binding; a dynamic system which can only be estimated rather than simulated in vitro. Intravenous SBE7-β-CD was also found to increase the urinary excretion of chlorpromazine (CPZ) and indinavir (IND). Unlike RIM, this occurrence was not attributed to glomerular filtration of intact complex from plasma. In the absence of any alteration of plasma pharmacokinetics, the increase in urinary excretion of CPZ and IND may be indicative of decreased tubular reabsorption of drug resulting from the formation of D-CD complexes within the renal tubules. In the case of CPZ, the binding of drug molecules and SBE7-β-CD was found to be dependent on total drug concentration, with self-association of CPZ at higher concentrations decreasing binding affinity with SBE7-β-CD. There was a 7-fold increase in the urinary solubility of IND despite a low binding constant ( 67 Mˉ¹). This was reflected in increased urinary concentrations of IND following co-administration with intravenous SBE7-β-CD. Pharmacokinetic studies demonstrated that early urinary concentrations of IND were often close to or above the equilibrium solubility of IND determined during phase solubility studies. This is consistent with the reported crystalluria associated with IND which has led to decreased clinical usage of IND. Chronic intravenous administrations of IND in rats (50 mg/kg daily for 15 days) resulted in characteristic changes to the renal histology. Co-administration of intravenous. SBE7-β-CD did not decrease the extent of these histological changes, however due to a number of experimental design-related factors, inconclusive results from the IND toxicity study presented in this work demonstrate a need for more specific studies to assess the impact of biological variability on the progression of renal damage.