Comparative pharmacokinetics of tetracaine using microdialysis, tape stripping, and systemic measurement

Faisal Al-Otaibi1, Arthure Tucker1,2, David Collier1, Terry Lee3, Badr AlJohani1, Atholl Johnston1. 1Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom, 2Vascular & Microvascular Unit, St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom, 3Analytical Unit, St George’s Hosbital, University of London, London, United Kingdom.

For most drugs the pharmacokinetics are characterized by systemic measurement of plasma concentrations. However, to be effective, local anaesthetics need to maintain high concentrations in the local tissues. The objective of this study was to determine the best approach to determine the pharmacokinetics of the local tetracaine following topical administration and to compare the drug concentration measurements using skin stripping with adhesive tape (TS)1, in microdialysis (MD) fluid2, and in plasma. Twelve healthy volunteers were successfully recruited. On two separate visits, 1mL of Ametop gel (4% w/w tetracaine) was administered topically to the volunteers’ forearm. On one visit microdialysis and systemic measurements were made and on the other skin stripping was used to determine drug absorption. There was a minimum of one-week gap in between visits. HPLC was used to measure tetracaine after tape stripping (UV detection) and the hydrolysis product p-butyl amino benzoic acid (BABA) in dialysate and plasma (MS-MS detection).Tetracaine was observed with higher concentration in stratum corneum by 3 fold compared with BABA concentrations in dialysate and 10 fold compared with plasma. The data were analysed for pharmacokinetic parameters of tetracaine and BABA, showed the higher AUC and Cmax for tetracaine in TS compared to BABA in MD and plasma (Mean AUC0-4: 1454, 0.91 and 0.21 nM/L.min: Mean Cmax (0-4), 862, 0.44 and 0.11 nM/L, respectively). Wilcoxon Signed Rank Test, shows a significant statistic difference (p = 0.002) between TS tmax and plasma tmax, the median tmax was higher in plasma (IQR -52.5 min, 95% CI -105 to -30) compared with tape samples, but not for MD. TS study showed low variable data compared to plasma and most variable for MD (CV%; AUC0-4, 24, 63, and 85%: Cmax (0-4), 42, 60, 80%, respectively). AUC and Cmax (Bartlett’s test, p = 0.002, and 0.026, respectively; and Levene’s test, p = 0.031 for AUC). However, result showed that no existence of any correlation between the three methods in PK parameters (P value>0.05) table 1. Table1: Pearson correlation coefficient (r) of AUC, Cmax, and tmax, between TS, MD, and plasma methods, of skin study.

Topical tetracaine was safe and decreased pain in the healthy subjects. The study results demonstrated that skin stripping with adhesive tape and microdialysis are useful methods of pharmacokinetics assessment of topical drugs. However, in comparison with plasma both skin stripping with adhesive tape and microdialysis are considerably more variable. Nevertheless both methods measure local drug concentrations and thus may be more relevant measurements for assessing the pharmacokinetics of drugs such as local anaesthetics.

1. Weigmann, H., Lademann, J., V Pelchrzim, R., Sterry, W., Hagemeister, T., Molzahn, R., Schaefer, M., Lindscheid, M., Schaefer, H. & Shah, V. P. 1999. Bioavailability of clobetasol propionate-quantification of drug concentrations in the stratum corneum by dermatopharmacokinetics using tape stripping. Skin Pharmacol Appl Skin Physiol, 12, 46-53.
2. Kreilgaard, M. 2002. Assessment of cutaneous drug delivery using microdialysis. Adv Drug Deliv Rev, 54 Suppl 1, S99-121.