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Titolo:
ANTIPROGESTIN PHARMACODYNAMICS, PHARMACOKINETICS, AND METABOLISM - IMPLICATIONS FOR THEIR LONG-TERM USE
Autore:
JANG GR; BENET LZ;
Indirizzi:
UNIV CALIF SAN FRANCISCO,DEPT BIOPHARMACEUT SCI,513 PARNASSUS AVE SANFRANCISCO CA 94143 UNIV CALIF SAN FRANCISCO,DEPT BIOPHARMACEUT SCI SAN FRANCISCO CA 94143
Titolo Testata:
Journal of pharmacokinetics and biopharmaceutics
fascicolo: 6, volume: 25, anno: 1997,
pagine: 647 - 672
SICI:
0090-466X(1997)25:6<647:APPAM->2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN PROGESTERONE-RECEPTOR; ORALLY ACTIVE PROSTAGLANDIN; LOW-DOSE MIFEPRISTONE; BREAST-CANCER-CELLS; EARLY-PREGNANCY; HUMAN-LIVER; P-GLYCOPROTEIN; MENSTRUAL-CYCLE; MAMMARY-TUMORS; POSTCOITAL CONTRACEPTION;
Keywords:
ANTIPROGESTINS; MIFEPRISTONE; LILOPRISTONE; ONAPRISTONE; RECEPTOR BINDING; SATURABLE PROTEIN BINDING; CYTOCHROME P450 3A4; P-GLYCOPROTEIN; DRUG-DRUG INTERACTIONS;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
132
Recensione:
Indirizzi per estratti:
Citazione:
G.R. Jang e L.Z. Benet, "ANTIPROGESTIN PHARMACODYNAMICS, PHARMACOKINETICS, AND METABOLISM - IMPLICATIONS FOR THEIR LONG-TERM USE", Journal of pharmacokinetics and biopharmaceutics, 25(6), 1997, pp. 647-672

Abstract

Antiprogestins represent a relatively new and promising class of therapeutic agents that could have significant impact on human health and reproduction. In the present work, the pharmacodynamics, pharmacokinetics, and metabolism of mifepristone (MIF), lilopristone (LIL), and onapristone (ONA) in humans are reviewed, and characteristics bearing important clinical implications are discussed. Although MIF has gained notoriety as an ''abortion pill, '' antiprogestins may more importantly prove effective in the treatment of endometriosis, uterine leiomyoma, meningioma, cancers of the breast and prostate, and as contraceptive agents. MIF pharmacokinetics display nonlinearities associated with saturable plasma protein (a I-acid glycoprotein, AAG) binding and characterized by lack of dose dependency for parent drug plasma concentrations (for doses greater than 100 mg) and a zero-order phase of elimination. LIL and ONA pharmacokinetics are less well characterized but ONA does not appear to bind AAG and displays a much shorter t(1/2) than the other agents. The three antiprogestins are substrates of cytochrome P450 (CYP) 3A4, an enzyme exceedingly important in human xenobiotic metabolism. Even more implicative of likely drug-drug interactions subsequent to their long-term administration are recent data from our laboratory indicating that they inactivate CYP3A4 in a cofactor- and time-dependent manner, suggesting that complexation and induction of the enzyme may occur in vivo via protein stabilization. Moreover, it has been demonstrated that MIF increases CYP3A4 mRNA levels in human hepatocytesin primary culture, indicative of message stabilization and/or transcriptional activation of CYP3A4 expression. Finally, MIF has also been shown to inhibit P-glycoprotein function. Whether LIL and ONA share these latter two characteristics with MIF has not yet been determined but they illustrate properties that, in addition to diminished antiglucocorticoid activities and altered pharmacokinetic characteristics, warrant consideration during the development of these and newer antiprogestational agents.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/01/20 alle ore 21:27:39