Kirti H. Valia

Long-Term Permeation Kinetics of Estradiol: (III) Kinetic Analyses of the Simultaneous Skin Permeation and Bioconversion of Estradiol Esters

AbstractThe skin permeation system developed earlier in this laboratory was utilized to study the kinetics of the simultaneous skin permeation and bioconversion of 5 estradiol esters. The equilibrium solubility of estradiol esters in the lipophilic silicone fluid and in hydrophilic PEG 400/saline solution was found to be dependent upon the alkyl chain length of the esters. Estradiol-3,17-diacetate had a greater solubility in silicone fluid and a lower solubility in PEG 400/saline solution than estradiol-17-acetate. The (skin/silicone fluid) partition coefficients were observed to decrease as the alkyl chain increased in length. During the course of skin permeation, the estradiol esters were metabolized by esterase to regenerate estradiol. The rate of appearance of estradiol from the estradiol esters was observed to be dependent upon the ester concentration on stratum corneum surface and to follow the order of: diacetate > valerate > heptanoate > cypionate > acetate. From the dermal uptake and metabolism s...

Long-term permeation kinetics of estradiol: (IV) A theoretical approach to the simultaneous skin permeation and bioconversion of estradiol esters

AbstractA theoretical non-steady-state treatment was developed to analyze the kinetics of metabolism during the course of dermal uptake or skin permeation of estradiol esters across the hairless mouse skin. The first-order rate constants for the metabolism reaction of estradiol acetate → estradiol and estradiol diacetate → estradiol acetate → estradiol were determined. The theoretical drug concentration profile calculated from the present model was found to be agreed reasonably well with the experimental data determined in the early stage of skin uptake/metabolism studies (<24 hr). For the skin permeation of estradiol acetate and diacetate and their concurrent metabolism, the experimental Q vs. t profiles were also observed to agree well with the theoretical results for a period of up to 28 hr. A deviation was observed at later phase of experiments, which can be attributed to the reduction in enzyme activity during the permeation studies, possibly due to the result of skin aging.

Disposition of 14C-Quinelorane in Dogs Following Oral or Intravenous Dosing and Transdermal Patch Application

AbstractA transdermal patch was developed to circumvent the emesis associated with the oral and intravenous administration of a dopamine agonist, quinelorane, to dogs.Approximate steady-state plasma concentrations were achieved following the daily application of a transdermal patch for 7 days. Each dog received between 0.1 and 0.2 mg/kg per day from the transdermal patch.At steady-state conditions, dogs received either a single oral dose of 14C-quinelorane at 0.1 mg/kg, a bolus intravenous dose of 0.03 mg/kg or had a transdermal patch containing the radioactive free base, 14C-quinelorane, applied to their abdomens for 24 hours; the approximate dose was 0.18 mg/kg.The plasma pharmacokinetics were measured by liquid scintillation counting and ELISA.The systemic bioavailability of quinelorane, as measured by the ELISA, was 30%, indicative of first-pass metabolism.The radioactive urinary metabolite profile was similar for all three routes of administration. Principal entities in the urine were quinelorane, th...