SCAN: In vitro models for bioavailability: evaluation of drug-drug interactions

SCAN Seminar

Title: In vitro models for bioavailability: evaluation of drug-drug interactions

Speaker: Hugo Serra, Pharmacokinetics and Biopharmaceutical Analysis Laboratory

Abstract

In recent years the issue of drug-drug interactions has generated significant concern within the pharmaceutical industry and among US and European regulatory authorities. The co-administration of different drugs or dietary supplements can affect the pharmacokinetics and consequently the therapeutic outcome of a drug due to alterations in its absorption, distribution, metabolism and excretion (ADME).

Many adverse drug interactions result from inhibition or induction of metabolizing enzymes or transporter proteins, such as p-glycoprotein.

Clopidogrel is a potent antiplatelet and antithrombotic agent which acts as a pro-drug, requiring oxidation by the hepatic cytochrome P450 and subsequent hydrolysis to generate the active metabolite, a thiol compound. However, after oral administration to humans, the main metabolite circulating in plasma (85 %) is the inactive carboxylic acid derivative which results from ester hydrolysis by carboxylesterases.

Flavonoids have been reported to affect positively ester drug absorption due to esterase inhibition. Being present in several dietary supplements and over the counter medicines, the relevance of such interactions should not be ignored.
The enzymatic inhibition of clopidogrel hydrolysis by some flavonoids present in our diet and in some pharmaceutical formulations was evaluated in this study. The flavonoid aglycones diosmetin and hesperitin showed a strong inhibitory effect on porcine liver carboxylesterase and also in primary rat hepatocytes. Kinetic parameters KM and Ki were determined.

Since hydrolysis of the ester bond of clopidogrel leads to its inactivation, it can be expected that the inhibition of the carboxylesterase activity would increase the amount of the parent drug available for absorption and oxidation and consequently increase therapeutic outcome and eventual side effects.

Studies of inhibition of the CYP450 by the same flavonoids should also be conducted as future work, to understand the overall effect of dietary supplements containing flavonoids in clopidogrel hepatic metabolism.

SHORT CV

1997-2003: Degree in Technological Chemistry by Faculdade Ciências - Universidade Lisboa.
2002-2003: Undergraduate training at the Chemistry of Natural Products group at INETI, Lisboa.
2003-2004: Post-graduation course in Applied Analytical Chemistry, FCUL.
2004-2005: Junior Researcher at the Chromatography and Capillary Electrophoresis Laboratory, FCUL, in an FCT financed project "Cost-Effective Monitoring of Endocrine Disruptors in the Marine Environment".
Since 2005: PhD fellowship by Fundação para a Ciência e Tecnologia and Laboratório Medinfar, on "Development, aplication and validation of in vitro models for the evaluation of the bioavailability and bioequivalence of drugs", at the Pharmacokinetics and Biopharmaceutical Analysis Laboratory, ITQB/IBET, under the supervision of Dr. Ana Luísa Simplício and Dr. Rosário Bronze.