不知是你的页码错了,还是这不是你要找的。很遗憾我载不了全文。
Title: Clinical pharmacokinetics of lamivudine
Author(s): Johnson MA, Moore KHP, Yuen GJ, Bye A, Pakes GE
Source: CLINICAL PHARMACOKINETICS 36 (1): 41-66 JAN 1999
Document Type: Review
Language: English
Cited References: 69 Times Cited: 65
Abstract: Lamivudine (3TC), the negative enantiomer of 2'-deoxy-3'-thiacytidine, is a dideoxynucleoside analogue used in combination with other agents in the treatment of human immunodeficiency virus type 1 (HIV-1) infection and as monotherapy in the treatment of hepatitis B virus (HBV) infection. Lamivudine undergoes anabolic phosphorylation by intracellular kinases to form lamivudine 5'-triphosphate, the active anabolite which prevents HIV-1 and HBV replication by competitively inhibiting viral reverse transcriptase and terminating proviral DNA chain extension.
The pharmacokinetics of lamivudine are similar in patients with HIV-1 or HBV infection, and healthy volunteers. The drug is rapidly absorbed after oral administration, with maximum serum concentrations usually attained 0.5 to 1.5 hours after the dose. The absolute bioavailability is approximately 82 and 68% in adults and children, respectively. Lamivudine systemic exposure, as measured by the area under the serum drug concentration-time curve (AUC), is not altered when it is administered with food.
Lamivudine is widely distributed into total body fluid, the mean apparent volume of distribution (Vd) being approximately 1.3 L/kg following intravenous administration. In pregnant women, lamivudine concentrations in maternal serum, amniotic fluid, umbilical cord and neonatal serum are comparable, indicating that the drug diffuses freely across the placenta. In postpartum women lamivudine is secreted into breast milk. The concentration of lamivudine in cerebrospinal fluid (CSF) is low to modest, being 4 to 8% of serum concentrations in adults and 9 to 17% of serum concentrations in children measured at 2 to 3 hours after the dose. In patients with normal renal function, about 5% of the parent compound is metabolised to the trans-sulphoxide metabolite, which is pharmacologically inactive.
In patients with renal impairment, the amount of trans-sulphoxide metabolite recovered in the urine increases, presumably as a function of the decreased lamivudine elimination. As approximately 70% of an oral dose is eliminated renally as unchanged drug, the dose needs to be reduced in patients with renal insufficiency. Hepatic impairment does not affect the pharmacokinetics of lamivudine. Systemic clearance following single intravenous doses averages 20 to 25 L/h (approximately 0.3 L/h/kg). The dominant elimination half-life of lamivudine is approximately 5 to 7 hours, and the in vitro intracellular half-life of its active 5'-triphosphate anabolite is 10.5 to 15.5 hours and 17 to 19 hours in HIV-1 and HBV cell lines, respectively.
Drug interaction studies have shown that trimethoprim increases the AUC and decreases the renal clearance of lamivudine, although lamivudine does not affect the disposition of trimethoprim. Other studies have demonstrated no significant interaction between lamivudine and zidovudine or between lamivudine and interferon-alpha-2b. There is limited potential for drug-drug interactions with compounds that are metabolised and/or highly protein bound.
KeyWords Plus: IMMUNODEFICIENCY-VIRUS INFECTION; HEPATITIS-B-VIRUS; ZIDOVUDINE COMBINATION THERAPY; CD4 CELL COUNTS; HIV-INFECTION; REVERSE-TRANSCRIPTASE; CUBIC MILLIMETER; PHASE I/II; 2'-DEOXY-3'-THIACYTIDINE BCH-189; (-)-2'-DEOXY-3'-THIACYTIDINE 3TC
Addresses: Johnson MA (reprint author), Glaxo Wellcome Res & Dev Inc, Dept Clin Pharmacol, Greenford Rd, Greenford UB6 0HE, Middx England
Glaxo Wellcome Res & Dev Inc, Dept Clin Pharmacol, Greenford UB6 0HE, Middx England
Glaxo Wellcome Inc, Res Triangle Pk, NC 27709 USA
E-mail Addresses: maj@glaxowellcome.co.uk
Publisher: ADIS INTERNATIONAL LTD, 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 10, NEW ZEALAND
Subject Category: PHARMACOLOGY & PHARMACY
IDS Number: 162WG
ISSN: 0312-5963
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