Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
THE ROLE OF CYTOCHROME-P450 3A4 IN ALFENTANIL CLEARANCE - IMPLICATIONS FOR INTERINDIVIDUAL VARIABILITY IN DISPOSITION AND PERIOPERATIVE DRUG-INTERACTIONS
Autore:
KHARASCH ED; RUSSELL M; MAUTZ D; THUMMEL KE; KUNZE KL; BOWDLE TA; COX K;
Indirizzi:
UNIV WASHINGTON,DEPT ANESTHESIOL,BOX 356540 SEATTLE WA 98195 UNIV WASHINGTON,DEPT MED CHEM SEATTLE WA 98195 UNIV WASHINGTON,DEPT PHARMACEUT SEATTLE WA 98195 PUGET SOUND VET AFFAIRS HLTH CARE SYST,ANESTHESIOL SERV SEATTLE WA 00000
Titolo Testata:
Anesthesiology
fascicolo: 1, volume: 87, anno: 1997,
pagine: 36 - 50
SICI:
0003-3022(1997)87:1<36:TROC3I>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER-MICROSOMES; GENETIC-POLYMORPHISM; CYP3A ACTIVITY; PHARMACOKINETIC DATA; URINARY-EXCRETION; EPOXIDE HYDROLASE; ENZYME-INDUCTION; METABOLISM; INFUSION; AGE;
Keywords:
ANALGESICS, OPIOID, ALFENTANIL, FENTANYL, SUFENTANIL, REMIFENTANIL; ANESTHETICS, INTRAVENOUS, ALFENTANIL, FENTANYL, MIDAZOLAM, REMIFENTANIL, SUFENTANIL; ENZYMES, CYTOCHROME P450 3A4; INTERACTIONS, DRUG; PHARMACOKINETICS, AGING, COMPUTER SIMULATIONS, CONTEXT-SENSITIVE HALF-TIME, VARIABILITY, WOMEN; RIFAMPIN; TROLEANDOMYCIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
59
Recensione:
Indirizzi per estratti:
Citazione:
E.D. Kharasch et al., "THE ROLE OF CYTOCHROME-P450 3A4 IN ALFENTANIL CLEARANCE - IMPLICATIONS FOR INTERINDIVIDUAL VARIABILITY IN DISPOSITION AND PERIOPERATIVE DRUG-INTERACTIONS", Anesthesiology, 87(1), 1997, pp. 36-50

Abstract

Background: There is considerable unexplained variability in alfentanil pharmacokinetics, particularly systemic clearance. Alfentanil is extensively metabolized in vivo, and thus systemic clearance depends on hepatic biotransformation. Cytochrome P450 3A4 was previously shown tobe the predominant P450 isoform responsible for human liver microsomal alfentanil metabolism in vitro. This investigation tested the hypothesis that P450 3A4 is responsible for human alfentanil metabolism and clearance in vivo. Methods: Nine healthy male volunteers who provided institutionally approved written informed consent were studied in a three-way randomized crossover design. Each subject received alfentanil (20 mu g/kg given intravenously) 30 min after midazolam (1 mg injectedintravenously) on three occasions: control; high P450 3A4 activity (rifampin induction); and low P450 3A4 activity (selective inhibition bytroleandomycin). Midazolam is a validated selective in vivo probe forP450 3A4 activity. Venous blood was sampled for 24 h and plasma concentrations of midazolam and alfentanil and their primary metabolites 1'-hydroxymidazolam and noralfentanil were measured by gas chromatography-mass spectrometry Pharmacokinetic parameters were determined by two-stage analysis using both noncompartmental and three-compartment models. Results: Plasma alfentanil concentration-time profiles depended significantly on P450 3A4 activity. Alfentanil noncompartmental clearancewas 5.3 +/- 2.3, 14.6 +/- 3.8, and 1.1 +/- 0.5 ml.kg(-1).min(-1), andelimination half-life was 58 +/- 13, 35 +/- 7, and 630 +/- 374 min, respectively, In participants with normal (controls), high (rifampin), and low (troleandomycin) P450 3A4 activity (means +/- SD; P < 0.05 compared with controls). Multicompartmental modeling suggested a time-dependent inhibition-resynthesis model for troleandomycin effects on P4503A4 activity, characterized as k(10)(t) = k(10) [1 - phi e(-alpha(t-t0))], where k(10)(t) is the apparent time-dependent rate constant, k(10) is the uninhibited rate constant, phi is the fraction of P450 3A4 inhibited, and cu is the apparent P450 3A4 reactivation rate. Alfentanil clearance was calculated as V-1.k(10) for controls and men receivingrifampin, and as V-1.average k(10)(t) for men receiving troleandomycin. This clearance was 4.3 +/- 2.1, 13.2 +/- 3.6, and 1.5 +/- 0.8 ml.kg(-1).min(-1), respectively, in controls and in men receiving rifampin or troleandomycin. There was a significant correlation (r = 0.97, P < 0.001) between alfentanil systemic clearance and P450 3A4 activity. Conclusions: Modulation of P450 3A4 activity by rifampin and troleandomycin significantly altered alfentanil clearance and disposition. These results strongly suggest that P450 3A4 is the major isoform of P450 responsible for clinical alfentanil metabolism and clearance. This observation, combined with the known population variability in P450 3A4 activity, provides a mechanistic explanation for the Interindividual variability In alfentanil disposition. Furthermore, known susceptibility of human P450 3A4 activity to induction and inhibition provides a conceptual framework for understanding and predicting clinical alfentanil drug interactions. Finally, human liver microsomal alfentanil metabolism in vitro is confirmed as an excellent model for human alfentanil metabolism in vivo.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 22:06:53