Piperazine pharmacokinetics

Further development in the chemistry of oxazolidinone antibacterials was based mainly on the assumption that the 4-pyridyl moiety of one of Dupont s lead compounds, E-3709, might be amenable to replacement by suitably saturated heterocyclic bioisosteres [48]. This assumption was based on an example in which successful replacement of the piperazine ring system in the quinolone antibacterials, such as ciprofloxacin, with a pyridine fragment, such as seen in Win-57273, results in improvement of both the antibacterial and the pharmacokinetic profiles of the compounds. Similarly, as in the case of ciprofloxacin and Win-57273, it was predicted that the presence of a small but highly electron-withdrawing fluorine atom would be tolerated at the meta position(s) of the central phenyl ring, and would confer enhanced antibacterial activity and/or other desirable properties to the targeted oxazolidinones, as shown in Fig. 3. 

B.4.2.2 Nonbenzodlazeptnes GG-NPD was used by Kivisto et al. (1999) to quantitate the nonbenzodiazepine anxiolytic buspirone and its major metabolite, l-(2-pyrimidinyl)-piperazine, using separate extraction methods and separate assays. The hmit of quantification in plasma for both compounds was 0.2 ng/mL, which makes this assay useful for pharmacokinetic studies of this compound (Kivisto et al., 1999). A rapid, simple method for analysis of buspirone in rat brain requiring a single extraction step followed by GC-NPD has also been described (Lai. et al., 1997). 

A. Fleaid, K.L. Locker, A.M. MacLeod, D. Morrison, C.R. Moyes, D. O Connor, A. Pike, M. Rowiey, M.G.N. Russell, B. Sohal, J.A. Stanton, S. Thomas, FI. Verrier, A.P. Watt, J.L. Castro, Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl) propyl)indoles gives selective human 5-FITid receptor ligands with improved pharmacokinetic profiles, J. Med. Chem. 42 (1999) 2087-2104. 

Zuideveld, K., Rusic-Pavletic, J., Maas, H., Peletier, L., VanDerGraaf, P., and Danhof, M., Pharmacokinetic-pharmacodynamic modeling of bus-pirone and its metabolite l-(2-pyrimidinyl)-piperazine in rats, Journal of Pharmacology and Experimental Therapeutics, Vol. 303, No. 3, 2002, pp. 1130-1137. 

The breakthrough in the development of quinolones came with the appearance of norfloxacin 6 [19], a second-generation quinolone which combined a 6-fluorine substituent with a piperazine ring in the 7-position of the basic compound. Additional quinolones then followed in rapid succession pefloxacin [20], enoxacin [21] and fleroxacin [22] (Fig. 14.5). Particular mention must be made of ciprofloxacin 8 [23-25], ofloxacin 5 [26,27] and its active enantiomer levofloxacin 7 [28]. These quinolones have a broad spectrum of activity, which also includes Gram-positive bacteria and Pseudomonas aeruginosa, as well as favorable pharmacokinetics. The rapid absorption of these compounds from the gastrointestinal tract and their effective tissue penetration also allows them to be used for the treatment of systemic infections. 

Kivisto KT, Lamberg TS, Neuvonen PJ. Interactions of buspirone with itraconazole and rifampicin effects on the pharmacokinetics of the active l-(2-pyrimidinyl)-piperazine metabolite of buspirone. Pharmacol Toxicol 1999 84(2) 94-7. 

The main difference between prazosin, terazosin, and doxazosin lies in their pharmacokinetic properties. As men-lloncd above, these differences are dictated by the nature of the acyl moiety attached to the piperazine ring. A comparison of these three agents with respect to their oral bioavailability, half-life, and duration of action is shown in Table 16-2. These drugs are metabolized extensively, with the me-taNiies excreted in the bile. 

Desipramine. The manufacturer of nefazodone reported that desipramine 75 mg daily did not change the pharmacokinetics of nefazodone 150 mg twice daily, but levels of the nefazodone metabolite, meta-chlorophenyl-piperazine, were increased by up to 50%. There was no change in the pharmacokinetics of desipramine or its metabolite. No specific dosage adjustments were said to be required on concurrent use. ... 

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