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Special Consideration of Drug Disposition
Published in Gary M. Matoren, The Clinical Research Process in the Pharmaceutical Industry, 2020
Although the single-dose drug metabolism study performed in the early days of a Phase I investigation can supply much badly needed information, such a study does not address itself to several important factors. These factors include the effect of route, dose, and regimen on drug disposition, the effect of saturation of protein drug binding sites, and the question of tolerance or sensitivity developing as a result of drug enzyme induction or inhibition.
Data Interpretation
Published in Francis L. S. Tse, James M. Jaffe, Preclinical Drug Disposition, 2017
Francis L. S. Tse, James M. Jaffe
It should be noted that chronic administration of a drug can result in altered biotransformation due to enzyme induction or inhibition. Thus, metabolism studies should be performed under both acute and chronic dosing conditions.
Rifampicin (Rifampin)
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
C. Alan, C. Street, Tony M. Korman
Induction of cytochrome P450 and other enzymes can lead to reduced plasma concentrations of co-administered drugs that are substrates of these enzymes. Individual pharmacokinetic variation, which results from drug interactions involving enzyme induction or inhibition, is in part determined by an individual’s genotype. In some cases, rifampicin co-administration may result in subtherapeutic levels of the interacting drug only in some individuals, depending on that individual’s genotype (Vormfelde et al., 2009). Details of reports of these and other rifampicin drug–drug interactions are included in reviews (Finch et al., 2002; Baciewicz et al., 2008; Baciewicz et al., 2013).
New anti-seizure medication for elderly epilepsy patients - a critical narrative review
Published in Expert Opinion on Pharmacotherapy, 2021
A Rohracher, G. Kalss, G. Kuchukhidze, C. Neuray, M. Leitinger, J. Höfler, R. Kreidenhuber, F. Rossini, K. Volna, M. Mauritz, N. Poppert, S. Lattanzi, F. Brigo, E. Trinka
Data available on PER in the elderly are very limited. So far, three studies provided encouraging results in this patient population [105–107], reporting high efficacy and no increased risk of AEs. As in young patients, dizziness and somnolence are the most common AEs in the elderly, and they can be successfully controlled by slow up-titration, low target doses and bed – time administration. Once daily use at bedtime can also increase compliance and adherence to treatment. Measurement of PER plasma levels, which is now increasingly available, can further help to identify the appropriate target dose for elderly patients. The overall pharmacokinetic profile of PER is favorable as it does not affect co-administered drugs to a relevant extent through enzyme induction or inhibition. The availability of an oral suspension, which was approved by the FDA in April 2016 and by the EMA in September 2016 facilitates the use of PER in patients having difficulties swallowing or even in patients with impaired consciousness.
A hybrid model to evaluate the impact of active uptake transport on hepatic distribution of atorvastatin in rats
Published in Xenobiotica, 2020
Priyanka Kulkarni, Ken Korzekwa, Swati Nagar
Drug transporters can complicate drug disposition as well as the safety and efficacy profiles of drugs (Giacomini et al., 2010; Shitara et al., 2006). Drug clearance and distribution can be impacted by active uptake of drugs into eliminating organs, as well as efflux out of the body, for example with biliary and renal excretion (Watanabe et al., 2009b). Uptake transporters can increase intracellular drug concentrations, thereby increasing the overall tissue distribution of the drug. Altered drug disposition in turn can affect the efficacy and toxicity profiles of drugs, and lead to drug-drug interactions (Hirano et al., 2006; Izumi et al., 2015). The organic anion transporting polypeptide (OATP) family of transporters has emerged as a determinant of drug disposition (Maeda et al., 2006; Shitara et al., 2013). These transporters catalyze the uptake of organic anions into the intestine and the liver, among other tissues. In the liver, predicted intracellular concentrations can be markedly higher than unbound plasma concentrations due to OATP activity (Hirano et al., 2004; Kulkarni et al., 2016; Menochet et al., 2012a,b). This may be especially important for drugs cleared primarily by the liver. In addition to increased clearance, higher intracellular concentrations can increase the likelihood of drug interactions due to enzyme induction or inhibition. For these reasons, it is important to understand and be able to predict the impact of transporters on intracellular and plasma drug disposition.
Drug metabolic stability in early drug discovery to develop potential lead compounds
Published in Drug Metabolism Reviews, 2021
Siva Nageswara Rao Gajula, Nimisha Nadimpalli, Rajesh Sonti
For a successful drug design, identifying an optimum combination of several properties is the critical component. Therefore, the DMPK (Drug metabolism and pharmacokinetics) expert's responsibility lies with optimizing the drug plasma t1/2, leading to an increase in the drug's metabolic stability and renal clearance. On the other hand, it is crucial to consider essential parameters such as elimination or reducing first-pass metabolism, enzyme induction, enzyme inhibition, and reactive or toxic metabolites (Kumar and Surapaneni 2001). In general, decreasing the lipophilicity or incorporation of stable, functional groups at labile metabolic sites of a drug substance enhances that compound's metabolic stability (Humphrey and Smith 1992). The binding of drug molecules to the enzyme occurs through hydrophobic interactions, and hence decreasing the lipophilicity of the drug results in the reduction of the favorable binding interactions. Introducing the isosteric atoms or functional groups leads to an increase in polarity and is the best suitable approach to decrease the lipophilicity of a lead compound. Also, introducing the heteroatom in the benzene ring can increase the polarity of the compound. For instance, incorporating a nitrogen atom in a benzene ring converts the benzene moiety to more polar pyridine (Tagat et al. 2001). Blocking metabolically labile groups is a promising approach to enhance metabolic stability. For example, the sites like benzylic or allylic positions that are potentially labile to oxidation can be blocked by incorporating halogen atoms on the carbon atom of that site or by isostere replacement of benzylic CH2 (Palani et al. 2002). Modification of metabolically labile groups is another elegant approach to improve metabolic stability. In addition to oxidation, functional groups can undergo hydrolysis by esterases and amidases, a typical process in the liver. For example, the ester linkage can be replaced by an amide linkage to improve the stability for esterase activity (Blanchard et al. 2002). These traditional approaches may sometimes reduce the biological activity of the lead compound.