Stereochemical aspects of drug action and pharmacokinetics

Abstract

The action and fate of drugs in the organism are determined by their interactions with endogenous macromolecules which are predominantly chiral in character. Consideration of the stereochemical aspects of drug action and pharmacokinetics has been intensified since the 1980s and has led to extensive documentation of significant differences existing between stereoisomeric forms of a single drug. Enantiomers can posses different efficacies, exhibit different pharmacological and toxicological effects, and consequently be characterized by different safety profiles. The growing wealth of evidence on the importance of stereochemistry, regulatory incentives, development of asymmetric synthesis methods and analytics - all contributed to fundamental changes in the way new chiral drugs are developed, tested, registered and market-managed. Today, enantiomers need to be treated as separate chemical entities and investigated correspondingly. Development of single enantiomer drugs can facilitate the reduction of total dose of xenobiotic administered to patients; improve the accuracy of doseresponse estimation; simplify pharmacokinetic studies and therapeutic monitoring. The stereochemical characteristics of biologically active compounds should, therefore, be considered from the earliest stages of drug development. Based on the established impact of stereochemistry, a single enantiomer formulation should be favored, whenever justified.

Dejstvo i sudbina leka u organizmu zavise od hiralnosti samih lekova kao i endogenih makromolekula sa kojima stupaju u interakciju. Razmatranje stereohemijskih aspekata dejstva i farmakokinetike lekova intenzivirano je početkom 80-tih godina prošlog veka i doprinelo je opsežnom dokumentovanju značajnih razlika između stereoizomernih oblika jednog leka. Enantiomeri tako mogu posedovati različitu efikasnost, mogu ispoljavati drugačije farmakološke i toksikološke efekte i sledstveno mogu imati različite bezbednosne profile. Sve veći broj dokaza o važnosti stereohemije, podsticaji regulatornih agencija, razvoj metoda asimetrične sinteze i analitike - doveli su do suštinskih promena u načinu na koji se novi hiralni lekovi razvijaju, ispituju, registruju i tržišno plasiraju. Enantiomere je danas neophodno tretirati kao zasebne entitete i zasebno ih ispitivati. Razvoj enantiomerno čistih formulacija lekova može omogućiti smanjenje ukupne količine ksenobiotika kojoj se pacijent izlaže, omogućiti precizniju procenu odnosa doze i efekta, pojednostaviti farmakokinetička ispitivanja i terapijski monitoring. Stoga je stereohemijske osobine biološki aktivnih jedinjenja neophodno razmatrati od najranijih faza procesa stvaranja novog leka da bi se blagovremeno napravio racionalan izbor jednog enantiomera za terapijsku primenu, kad god je to opravdano.