12 - substrates pharmacokinetic studies

Nifedipine was one of the first CYP3A4 substrates to be identified (167,168) and has been the subject of a large number of drug-drug interaction studies both in vitro and in vivo. Pharmacokinetic studies with nifedipine clearly identify inhibitors, such as itraconazole (169) and grapefruit juice (170), and inducers, such as the barbiturates (171) and rifampin (172). 

These results show that acipimox acts to inhibit cAMP-stimulated hpolysis through suppression of intracellular cAMP levels, with a subsequent decrease in PKA activity. The anti-lipolytic activity of acipimox is associated with a quantitative shift of HSL from the LD to the cytosol in rat adipocytes, suggesting that, by decreasing intracellular cAMP levels, acipimox can reduce the association of HSL with TAG substrate of the LD. Pharmacokinetic studies show that the plasma concentration of acipimox in man after a single 250 mg oral dose reaches 33 gM, and remains above 7 gM for 6-8 h [448]. In comparison, acipimox is a potent anti-lipolytic agent at a concentration of 10 gM and above, in human adipose tissue stimulated maximally and sub-maximally by isoproterenol [449]. Thus, plasma acipimox levels correlate well with its in vitro effect on hpolysis and cAMP synthesis in rat adipocytes. 

A pharmacokinetic study found no interaction between cisapride (a cytochrome P450 isoenzyme CYP3A4 substrate) and eplerenone. ... 

No 3-azido, 3-amino, or Boc-protected mannosamine analogs 12 were accepted by the enzyme (Figure 5.11) [98] which suggests that the presence of a 3-hydroxyl group is a necessary precondition for substrates of the aldolase. Likewise, conformationally inflexible acrylate 13 was not accepted in cleavage direction. By use of fluoropyruvate 15 as the donor substrate a series of dia-stereomeric 3-deoxy-3-fluoro ulosonic acids such as 16 has been prepared in good yields (>49%) from pentoses or hexoses [82]. Such products are attractive for non-invasive in-vivo pharmacokinetic studies by NMR tomography ( F derivatives) or positron-emission spectroscopy ( F derivatives). 

Dopamine, a vasodilator, has been widely used for treatment of acute circulatory failure. However, since dopamine is rapidly metabolized when administered orally, its use has been limited to intravenous infusion. Murata et al., studied the bioavailability and the pharmacokinetics of orally administered dopamine (DA). The oral administration of DA to dogs resulted in an absolute bioavailability of approximately 3%. To minimize the extensive first-pass metabolism of DA, a dopamine prodrug, V-(/V-acetyl-l-mcLhionyl)-o,o-bis(cLhoxycarbonyl)dopamine (TA-870), was synthesized [28] (Fig. 6). Since DA is a substrate for both mono-... 

For other efflux transporters such as BCRP (ABCG2), human pharmacokinetic and pharmacodynamic data are currently rare. However, an investigation of the influence of polymorphisms in ABC-transporter genes on the accumulation of nelfinavir in peripheral blood mononuclear cells (PBMCs) revealed no associations between the polymorphisms in the transporters analyzed and the accumulation of nelfinavir in the PBMCs [151], A second study in patients clearly demonstrated an increase in the AUC of the orally and intravenously administered BCRP substrate topotecan when it is given with GF120918, an inhibitor of P-glycoprotein and BCRP [152],... 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

To Study interactions between proteins and drugs, an available tool is the Drug Absorption, Distribution, Metabolism, and Excretion (ADME) Associated Protein Database (see Table 1.5). The database contains information about relevant proteins, functions, similarities, substrates and hgands, tissue distributions, and other features of targets. Eor the understanding of pharmacokinetic (PK) and pharmacodynamic (PD) features, some available resources are listed in Table 1.5. For example, the Pharmacokinetic and Pharmacodynamic Resources site provides links to relevant software, courses, textbooks, and journals (see Note 5). For quantitative structure-activity relationship (QSAR), the QSAR Datasets site collects data sets that are available in a structural format (see Table 1.5). 

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