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Research ArticleArticle

Nonlinear Pharmacokinetics of Efavirenz (DMP-266), a Potent HIV-1 Reverse Transcriptase Inhibitor, in Rats and Monkeys

Suresh K. Balani, Laura R. Kauffman, Florencia A. deLuna and Jiunn H. Lin
Drug Metabolism and Disposition January 1999, 27 (1) 41-45;
Suresh K. Balani
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Laura R. Kauffman
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Florencia A. deLuna
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Jiunn H. Lin
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Abstract

Efavirenz (EFV, Sustiva, Stocrin, DMP-266, L-743,726) is a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Pharmacokinetics of EFV was studied in rats and monkeys, the safety assessment species. In rats, after 2 and 5 mg/kg i.v. administrations, the mean CLp,Vdss, and T1/2 were 67 ml/min/kg, 5.0 liters/kg, and 1 h, respectively. EFV was metabolized completely, and the products were excreted almost exclusively via bile. At the higher dose of 15 mg/kg, theCLp was reduced by 36%, implying saturation of metabolism processes. A similar phenomenon occurred in monkeys, where the CLp declined by 60% as the i.v. dose was increased from 5 to 15 mg/kg. After oral dosing, the bioavailability of EFV in rats (10 mg/kg) and monkeys (2 mg/kg) was 16% and 42%, respectively. Higher doses in both species led to disproportionate increases in the AUC and higherTmax values, suggesting saturation of metabolism and/or prolongation of absorption. The delay inTmax was more pronounced in monkeys where the plasma concentrations reached plateaus and were sustained for 4 to 20 h. In rats, the prolongation of absorption was due to delayed gastric emptying as demonstrated by >10-fold slower transit of [14C]polyethylene glycol through the stomach of EFV-pretreated animals. The delayed gastric emptying in monkeys also was observed when the animals dosed at 160 mg/kg exhibited emesis, 8 h postdose, which was found to contain a substantial portion of the dose. These results demonstrated that in rats and monkeys, both delayed gastric emptying and saturation of metabolic processes played significant roles in the nonlinear pharmacokinetics of EFV.

Footnotes

  • Send reprint requests to: Suresh K. Balani, Ph.D., Department of Drug Metabolism, Merck Research Laboratories, WP75-100, West Point, PA 19486.

  • Abbreviations used are::
    RT
    reverse transcriptase
    EFV
    efavirenz, Stocrin, Sustiva, DMP 266, L-743,726, (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2(H)-3,1-benzoxazin-2-one
    DMSO
    dimethyl sulfoxide
    HPLC
    high-pressure liquid chromatography
    • Received April 16, 1998.
    • Accepted August 7, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (1)
Drug Metabolism and Disposition
Vol. 27, Issue 1
1 Jan 1999
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Research ArticleArticle

Nonlinear Pharmacokinetics of Efavirenz (DMP-266), a Potent HIV-1 Reverse Transcriptase Inhibitor, in Rats and Monkeys

Suresh K. Balani, Laura R. Kauffman, Florencia A. deLuna and Jiunn H. Lin
Drug Metabolism and Disposition January 1, 1999, 27 (1) 41-45;

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Research ArticleArticle

Nonlinear Pharmacokinetics of Efavirenz (DMP-266), a Potent HIV-1 Reverse Transcriptase Inhibitor, in Rats and Monkeys

Suresh K. Balani, Laura R. Kauffman, Florencia A. deLuna and Jiunn H. Lin
Drug Metabolism and Disposition January 1, 1999, 27 (1) 41-45;
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