IDENTIFICATION OF THE PHARMACOGENETIC DETERMINANTS OF ALFENTANIL METABOLISM - CYTOCHROME P-450-3A4 - AN EXPLANATION OF THE VARIABLE ELIMINATION CLEARANCE

被引:103
作者
YUN, CH
WOOD, M
WOOD, AJJ
GUENGERICH, FP
机构
[1] VANDERBILT UNIV,MED CTR,SCH MED,DEPT ANESTHESIOL,NASHVILLE,TN 37232
[2] VANDERBILT UNIV,MED CTR,SCH MED,DEPT PHARMACOL,NASHVILLE,TN 37232
[3] VANDERBILT UNIV,MED CTR,SCH MED,DEPT BIOCHEM,NASHVILLE,TN 37232
[4] VANDERBILT UNIV,MED CTR,SCH MED,CTR MOLEC TOXICOL,NASHVILLE,TN 37232
关键词
ANALGESICS; ALFENTANIL; ANESTHETICS; INTRAVENOUS; ALFENTAIL; BIOTRANSFORMATION; LIVER; MICROSOMES; METABOLISM; CYTOCHROMES P-450; P-450-3A4; P-450-2D6; GENETIC FACTORS; IMMUNOINHIBITION;
D O I
10.1097/00000542-199209000-00011
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
There is considerable variability in the elimination clearance of the opioid analgesic alfentanil. It has been shown previously that alfentanil clearance is independent of the polymorphic debrisoquine hydroxylase (P-450 2D6), and it is therefore of interest to identify the human cytochrome P-450 enzymes involved in noralfentanil formation, the primary reaction involved in the oxidative N-dealkylation at the piperidine nitrogen. Purified human P-450 3A4 showed appreciable catalytic activity, and yeast recombinant P-450 3A4 also showed alfentanil oxidation activity. When microsomes prepared from different human liver samples were compared, noralfentanil formation activity was well correlated (r = 0.95, P < 0.005) with nifedipine oxidation (a P-450 3A4 marker) hut not with markers of other P-450s, including phenacetin O-deethylation (P-450 1A2), chlorzoxazone 6-hydroxylation (P-450 2E1), and (S)-mephenytoin 4'-hydroxylation (a P-450 2C enzyme). Using antibodies that recognize specific human P-450 enzymes (immunoinhibition techniques), it was possible to demonstrate that anti-P-450 3A4 nearly completely inhibited alfentanil oxidation activity in the human liver microsomes, but no other antibodies showed a measurable inhibitory effect. Selective chemical inhibitors of P-450 3A4, gestodene and troleandomycin, inhibited as much as 90% of the microsomal noralfentanil formation activity, but other chemical inhibitors did not show a detectable inhibitory effect. 7,8-Benzoflavone inhibited as much as 90% of the alfentanil oxidation activity of the microsomal or reconstituted P450 3A4 system. This work indicates that P450 3A4 contributes significantly to human liver microsomal alfentanil oxidation, whereas P450 2D6 does not contribute. Human P450 3A4 metabolizes many clinically important substrates, including nifedipine, cyclosporin, midazolam, lidocaine, and quinidine, and is induced by barbiturates and some antibiotics. Therefore, the possibility exists for pharmacokinetic interactions between alfentanil and other concomitantly administered drugs that are also substrates for, or inducers of, P450 3A4.
引用
收藏
页码:467 / 474
页数:8
相关论文
共 59 条
  • [1] LIDOCAINE METABOLISM IN HUMAN-LIVER MICROSOMES BY CYTOCHROME-P450IIIA4
    BARGETZI, MJ
    AOYAMA, T
    GONZALEZ, FJ
    MEYER, UA
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 1989, 46 (05) : 521 - 527
  • [2] INHIBITION OF ALFENTANIL METABOLISM BY ERYTHROMYCIN
    BARTKOWSKI, RR
    GOLDBERG, ME
    LARIJANI, GE
    BOERNER, T
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 1989, 46 (01) : 99 - 102
  • [3] ISOLATION AND SEQUENCE DETERMINATION OF A CDNA CLONE RELATED TO HUMAN CYTOCHROME-P-450 NIFEDIPINE OXIDASE
    BEAUNE, PH
    UMBENHAUER, DR
    BORK, RW
    LLOYD, RS
    GUENGERICH, FP
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (21) : 8064 - 8068
  • [4] BORK RW, 1989, J BIOL CHEM, V264, P910
  • [5] EXPRESSION OF A HUMAN-LIVER CYTOCHROME-P-450 PROTEIN WITH TOLBUTAMIDE HYDROXYLASE-ACTIVITY IN SACCHAROMYCES-CEREVISIAE
    BRIAN, WR
    SRIVASTAVA, PK
    UMBENHAUER, DR
    LLOYD, RS
    GUENGERICH, FP
    [J]. BIOCHEMISTRY, 1989, 28 (12) : 4993 - 4999
  • [6] CATALYTIC ACTIVITIES OF HUMAN LIVER CYTOCHROME-P-450-IIIA4 EXPRESSED IN SACCHAROMYCES-CEREVISIAE
    BRIAN, WR
    SARI, MA
    IWASAKI, M
    SHIMADA, T
    KAMINSKY, LS
    GUENGERICH, FP
    [J]. BIOCHEMISTRY, 1990, 29 (51) : 11280 - 11292
  • [7] RECENT DEVELOPMENTS IN HEPATIC DRUG OXIDATION - IMPLICATIONS FOR CLINICAL PHARMACOKINETICS
    BROSEN, K
    [J]. CLINICAL PHARMACOKINETICS, 1990, 18 (03) : 220 - 239
  • [8] COMBALBERT J, 1989, DRUG METAB DISPOS, V17, P197
  • [9] DISTLERATH LM, 1985, J BIOL CHEM, V260, P9057
  • [10] DISTLERATH LM, 1987, MAMMALIAN CYTOCHROME, V1, P133