Saliva versus Plasma Relative Bioavailability of Tolterodine in Humans: Validation of Class III Drugs of the Salivary Excretion Classification System.

Relative bioavailability study of tolterodine in healthy human volunteers was done using saliva and plasma matrices in order to investigate the robustness of using saliva instead of plasma as a surrogate for bioavailability and bioequivalence of class III drugs according to the salivary excretion classification system (SECS). Saliva and plasma samples were collected up to 16 h after 2 mg oral dose. Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis using Kinetica program V5. Human effective intestinal permeability was optimized by SimCYP program V13. Tolterodine falls into class III (High permeability/Low fraction unbound to plasma proteins) and hence was subjected to salivary excretion. A high pearsons correlation coefficient of 0.97 between mean saliva and plasma concentrations, and saliva/plasma concentrations ratio of 0.33 were observed. In addition, correlation coefficients and saliva/plasma ratios of area under curve and maximum concentration were 0.98, 0.95 and 0.42, 0.34 respectively. On the other hand, time to reach maximum concentration was higher in saliva by 2.37 fold. In addition, inter subject variability values in saliva were slightly higher than plasma leading to need for slightly higher number of subjects to be used in saliva studies (55 vs. 48 subjects). Non-invasive saliva sampling instead of invasive plasma sampling method can be used as a surrogate for bioavailability and bioequivalence of SECS class I drugs when adequate sample size is used.

Bioequivalence evaluation of two brands of lisinopril tablets (Lisotec and Zestril) in healthy human volunteers.

The bioequivalence of two brands of lisinopril 20 mg tablets was demonstrated in 28 healthy human volunteers after a single oral dose in a randomized cross-over study, conducted at ACDIMA Center for Bioequivalence and Pharmaceutical Studies, Amman, Jordan. Reference (Zestril, AstraZeneca, UK) and test (Lisotec, Julphar, UAE) products were administered to fasting volunteers on 2 treatment days separated by a 2-week washout period; blood samples were collected at specified time intervals, and the plasma was separated and analysed for lisinopril using a validated LC-MS/MS method at ACDIMA Laboratory. The pharmacokinetic parameters AUC(0-t), AUC(0- proportional), C(MAX), T(MAX), T(1/2) and the elimination rate constant were determined from the plasma concentration-time profiles for both formulations and were compared statistically to evaluate bioequivalence between the two brands, using the statistical modules recommended by the FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetic profiles and that Julphar's Lisotec is bioequivalent to Zestril of AstraZeneca, UK.

Comparative pharmacokinetics of two tablet formulations of Losartan: bioequivalence assessment.

The pharmacokinetic profiles of two brands of losartan 50 mg tablets were compared in 24 healthy adult volunteers after a single oral dose in a randomized cross-over study. The study was conducted at the ACDIMA Center for Bioequivalence & Pharmaceutical Studies, Amman, Jordan. The reference (Cozaar, MSD, The Netherlands) and test (Blosart, Julphar, UAE) products were administered to fasting volunteers. Blood samples were collected at specified time intervals, and the plasma separated and analysed for losartan and its active metabolite (losartan carboxylic acid) using a validated HPLC method with fluorescence detection. Pharmacokinetic parameters AUC(0-t), AUC(0-alpha), C(max), T(max), T(1/2), elimination rate constant, MRT, Cl/F and Vss/F were determined from plasma concentration-time profiles of both formulations and found to be in good agreement with reported values. Three parameters (AUC(0-t), AUC(0-alpha), and C(max)) were compared statistically to evaluate the bioequivalence between the two brands, using statistical modules recommended by the FDA. Analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range (80%-125%) for bioequivalence. Based on these statistical inferences it was concluded that the two formulations exhibited comparable pharmacokinetic profiles and that Julphar's Blosart is bioequivalent to Cozaar of MSD, The Netherlands.

Targeting of liposomes to HIV-1-infected cells by peptides derived from the CD4 receptor.

Liposomes can be targeted to HIV-infected cells by either reconstituting transmembrane CD4 in the membrane or covalently coupling soluble CD4 to modified lipids. We investigated whether synthetic peptides could be used as ligands for targeting liposomes. A synthetic peptide from the complementarity determining region 2 (CDR-2)-like domain of CD4 could bind specifically to HIV-infected cells and mediate the binding of peptide-coupled liposomes to these cells. A peptide from the CDR-3-like domain of CD4 inhibited HIV-induced syncytia formation, but failed to target liposomes to infected cells. This apparent discrepancy may be due to the requirement for a conformational change in the CD4 receptor for the CDR-3 region to interact with the HIV envelope protein. Our results demonstrate the feasibility of using synthetic peptides to target liposomes containing antiviral drugs to HIV-infected cells.