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Drugs in pregnancy and lactation
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Drug testing for fetal toxicity and teratogenicity is not only a test of the mother compound as there are circulating metabolites that may also reach the fetal compartment. Thus, we also test the metabolites of the drug. If the drug is a racemate, about twice as many chemical moieties are tested compared to an enantiomeric or non-stereospecific drug.
Targeting the Nervous System
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Salbutamol has the same potency as isoprenaline, but is 2000 times less active on the heart, and with a duration of action of 4 hrs; not being recognised by certain metabolic enzymes. Salbutamol became a market leader for treating asthma in 26 countries. It was marketed as a racemate, but the R-enantiomer is 68 times more active than the S-enantiomer, which also accumulates in the body to give side-effects. As a result, the R-enantiomer (levalbuterol) was marketed.
Mephobarbital
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Mephobarbital (MPB) (5-ethyl-l-methyl-5-phenylbarbituric acid) (la and lb, Fig. 1) is the 1-methyl derivative of phenobarbital (PB) (II, Fig. 1). N-methylation of PB introduces a center of chirality (asymmetry) at carbon-5, and MPB therefore exists as a pair of enantiomers (stereoisomers), R-mephobarbital (la, Fig. 1), which is levorotatory and S-mephobarbital (lb, Fig. 1) which is dextrorotatory (1). The drug is used clinically as the racemate (50% of each enantiomer). As such it is a white crystalline powder, weakly acidic (pK, = 7.8) and somewhat more lipid-soluble than PB.
Enantioselective in vitro ADME, absolute oral bioavailability, and pharmacokinetics of (−)-lumefantrine and (+)-lumefantrine in mice
Published in Xenobiotica, 2021
Bhavesh Babulal Gabani, Abhishek Dixit, Vinay Kiran, Ram Murthi Bestha, Balaji Narayanan, Nuggehally R. Srinivas, Ramesh Mullangi
To the best of our knowledge, this is the first report assessing the stereoselective pharmacokinetics including absolute bioavailability of LFN in any species. LFN isomers showed low oral bioavailability (7.18 and 7.11% for (−)-LFN and (+)-LFN, respectively). Furthermore, the plasma concentration versus time data suggested the occurrence of stereoselectivity in the pharmacokinetics of LFN regardless of the dosing route when the drug racemate was administered. While intravenous dosing showed minor occurrence of stereoselectivity in the plasma profiles of the two isomers when drug racemate was dosed, the oral administration of the racemic drug enhanced the stereoselectivity. Regardless of oral or intravenous dosing, the disposition favored higher levels of (+)-LFN isomer as compared to the other antipode when the drug racemate was dosed. A similar pharmacokinetic comparison between either (+)-LFN or (−)-LFN given as a pure isomer versus the corresponding isomers after racemic drug, clearly suggested that the levels were higher when given as the isomer as compared to the racemate. In general, the elimination of the two isomers were reasonably comparable between individual versus racemic drug administration as well as oral versus intravenous administration. One key implication of this finding is whether to consider of the development of a single isomer in therapy after confirming that there is a similar occurrence in human pharmacokinetics of LFN isomers.
Comparative toxicity and toxicokinetic studies of oxiracetam and (S)-oxiracetam in dogs
Published in Xenobiotica, 2019
Tian-tian Liu, Xin-miao Guo, Zu-yuan Rong, Xiang-feng Ye, Jin-feng Wei, Ai-ping Wang, Hong-tao Jin
As a consequence of the rapid advances in chiral synthesis and separation technologies, combined with new regulatory policies for chiral pharmaceuticals, chiral drugs have become an important focus for research and development of new molecular entities (Calcaterra & D'Acquarica, 2018; Nunez et al., 2009; Srinivas, 2004). Stereoisomers (enantiomers and diastereoisomers) not only differ from one another in their pharmacological effects, but also in their pharmacokinetic (adsorption, distribution, biotransformation, and excretion) profiles (Brocks, 2006; Hutt, 2007) and toxicological properties (Natarajan & Basak, 2011; Smith, 2009). Understanding the stereospecificity of in vitro and in vivo pharmacokinetics/toxicokinetics may assist in delineating the developmental path of the racemate and/or the pure enantiomers. The differential actions and toxicities determine enantiomer selection to maximize clinical effects or mitigate drug toxicity. Toxicological evaluation of chiral drugs, therefore, deserves increased attention.
The problem of racemization in drug discovery and tools to predict it
Published in Expert Opinion on Drug Discovery, 2019
Andrew Ballard, Stefania Narduolo, Hiwa O. Ahmad, David A. Cosgrove, Andrew G. Leach, Niklaas J. Buurma
Other studies have investigated the pharmacokinetic properties of enantiomers. Ketoprofen, 12, is a non-steroidal anti-inflammatory and its delivery via a transdermal route has been considered [20]. When used orally, it is delivered as a racemate but stereoselective skin permeation might favor its use as a single enantiomer for this alternative delivery route. Studies showed the racemate to be higher melting than the individual enantiomers and x-ray diffraction patterns support the racemate having a different solid form than the individual enantiomers suggesting that the two enantiomers co-crystallize and are both present in the unit cell. When 0.05 M solutions of each of the enantiomers were applied to mouse skin, no difference in permeation was detected between enantiomers or racemate. Further studies supported no stereoselectivity for skin permeability for ketoprofen.