Pharmacokinetics and saturable renal tubular secretion of zidovudine in rats

Patel, B. J.; Chu, Chung K.; Boudinot, F. Douglas

doi:10.1002/jps.2600780704

Cited by 50 publications

(40 citation statements)

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“…The pharmacokinetics of zidovudine in humans (4,8,26,27,29) and various animal species (5,11,12,25,31) have been studied extensively. Studies with humans have shown that zidovudine is eliminated rapidly, with a terminal half-life (t1l2) of approximately 1 h, and about 60 to 80% of a dose is cleared from the body primarily by metabolism to the 5'-O-glucuronide.…”

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confidence: 99%

Pharmacokinetics of the anti-human immunodeficiency virus nucleoside analog stavudine in cynomolgus monkeys

Kaul

Dandekar

1993

Antimicrob Agents Chemother

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Stavudine was administered (15 mg/kg of body weight) intravenously and orally to two monkeys in a randomized crossover study. Plasma and urine samples were analyzed for stavudine by high-performance liquid chromatography, and pharmacokinetic parameters were derived by a noncompartmental method. Total body clearance of stavudine was 0.64 liters/h/kg, with a steady-state volume of distribution of 0.68 liters/kg, a terminal half-life of 0.83 h, a urinary recovery of 44%, and an oral bioavailability of 80%. These values were reasonably similar to those reported for patients with AIDS or AIDS-related complex.Zidovudine was the first nucleoside analog approved for the treatment of AIDS (28). The pharmacokinetics of zidovudine in humans (4,8,26,27,29) and various animal species (5,11,12,25,31) have been studied extensively. Studies with humans have shown that zidovudine is eliminated rapidly, with a terminal half-life (t1l2) of approximately 1 h, and about 60 to 80% of a dose is cleared from the body primarily by metabolism to the 5'-O-glucuronide. Of the animals investigated, the monkey has been identified as an appropriate animal model for zidovudine pharmacokinetics in humans (3, 5, 10, 11, 18) compared with other animals (11,18,19,37). Likewise, the monkey appears to be an acceptable model for didanosine pharmacokinetics in humans (33).Of several dideoxynucleoside analogs with in vitro antihuman immunodeficiency virus activity, stavudine has emerged as a potent agent which is being evaluated currently in clinical trials for the treatment of human immunodeficiency virus infection (2,14,15,32). The pharmacokinetics of stavudine in humans (13,22,24) and various animal species (6,7,35,36,38) have been reported previously.Studies with rodents have shown that the t1l2 of stavudine ranged from 0.3 to 0.6 h, the urinary recovery was about 70 to 80%, and the oral bioavailability was in the range of 80 to 95%. Although the t1l2 of stavudine in rhesus monkeys (0.9 to 1.4 h) is comparable to that in humans (13,22,24), interestingly, its absolute bioavailability is only 42% (versus 80 to 90% in humans) and the fractional urinary elimination of unchanged drug has not been reported. Therefore, the pharmacokinetics, oral bioavailability, and urinary excretion of stavudine in cynomolgus monkeys were evaluated to determine whether it is an appropriate model for stavudine pharmacokinetics in humans.Two young adult male cynomolgus monkeys weighing 2

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confidence: 99%

Pharmacokinetics of the anti-human immunodeficiency virus nucleoside analog stavudine in cynomolgus monkeys

Kaul

Dandekar

1993

Antimicrob Agents Chemother

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“…At 20 mg/kg, CL R was 1.24 l/h/kg which was greater than the glomerular filtration rate (0.27 l/h/kg for rats) (Patel et al, 1989). Thus, it was demonstrated that the tubular secretion mediated by a transporter (P-gp) is the main eliminating pathway of etoposide in the kidney.…”

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confidence: 87%

An Evaluation Method for Nonlinear Local Disposition in Rat Liver and Kidney

Katō

Yamaoka²,

Takakura³

2004

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:A two-sampling sites method was developed to separately estimate the nonlinear local disposition in the liver and kidney by sampling blood simultaneously from the hepatic vein and an artery after intravenous administration. Using this method, it was attempted to predict the renal elimination from the systemic and hepatic elimination. Etoposide, a substrate of both P-glycoprotein and CYP3A, was used as a model drug. The blood samples from the hepatic vein and an artery were simultaneously taken from a rat after intravenous administration of etoposide at a dose of 20 or 80 mg/kg. At a dose of 20 mg/kg, the total clearance (CL), hepatic clearance (CL H ), and renal clearance (CL R ‫؍‬ CL ؊ CL H ), which were almost constant, were 2.82 ؎ 0.24, 0.742 ؎ 0.214, and 2.09 ؎ 0.34 l/h/kg, respectively. At a dose of 80 mg/kg, CL and CL R considerably decreased with an increase in plasma concentration, whereas CL H slightly decreased. By means of the two-sampling sites method, we estimated the local drug disposition in the liver and kidney. The present local pharmacokinetic method would be applicable to assess the local disposition of other drugs that are mainly metabolized in these organs.Drug transporters as well as drug-metabolizing enzymes play a critical role in the disposition and the elimination of xenobiotics. For example, P-glycoprotein (P-gp 1 ) is a prominent ATP-dependent efflux pump that has broad substrate specificity (Gottesman and Pastan, 1993). Cytochrome P450 is a key member of the group of phase I enzymes metabolizing many drugs, and it plays an important role in the first-pass metabolism of drugs after oral administration. P450s are mainly expressed in the liver, intestinal wall, and kidney (Ford and Hait, 1990;de Wildt et al., 1999). It is predicted that their substrates exhibit nonlinear pharmacokinetics in these organs.Etoposide, a podophyllotoxin derivative, is an antineoplastic agent that acts via inhibition of DNA topoisomerase II activity. Etoposide is commonly used in the treatment of neoplastic diseases such as smallcell lung cancer and Kaposi's sarcoma (Belani et al., 1994;Clark and Slevin, 1987). It is known that etoposide is a substrate of both P-gp (Kunta et al., 2000;Guo et al., 2002) and CYP3A (Kawashiro et al., 1998). Myelosuppression during clinical treatment is a major side effect of etoposide, which is caused by capacity-limited disposition. This side effect of etoposide tends to occur following coadministration with drugs that influence the expression and function of P-gp and CYP3A.In a recent study, the three-sampling sites method was proposed to separately estimate the local absorption kinetics and the hepatic firstpass metabolism by sampling blood from the portal and hepatic veins, and an artery (Ueda et al., 2002). In this method, the local intestinal absorption kinetics can be assessed by using the blood concentration difference between the portal vein and the systemic circulation after oral administration. ...

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“…Differences in the renal clearances of these nucleosides can be attributed to variances in the transport capacity, to affinity of the active secretion mechanism, or to differences in degree of passive tubular reabsorption. Previous studies have suggested that AZT does not undergo tubular reabsorption in rats (18 (14) also reported the absence of glucuronide or other metabolites in the urine of rats receiving D4T.…”

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confidence: 81%

Pharmacokinetics of 3'-fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine in rats

Boudinot

Smith

Funderburg

et al. 1991

Antimicrob Agents Chemother

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Concentrations of 3'-fluoro-3'-deoxythymidine (FDT) and 3'-deoxy-2',3'-didehydrothymidine (D4T) in plasma declined in a biexponential fashion. Total clearance of D4T (1.75 ± 0.22 liters/h/kg; mean ± standard deviation) was significantly greater than that of FDT (1.19 + 0.19 liters/h/kg) owing to greater renal and nonrenal clearances of the former. Steady-state volumes of distribution of FDT (1.20 + 0.12 liters/kg) and D4T (1.07 ± 0.15 liters/kg) were similar.The search for antiretroviral agents for the treatment of AIDS has yielded a number of compounds with selective in vitro antiviral activity. Compounds that inhibit human immunodeficiency virus type 1 reverse transcriptase, especially nucleoside analogs containing a 3'-azido,3'-fluoro or unsaturation, have proven to be particularly potent and selective. Among these are 3'-fluoro-3'-deoxythymidine (FDT; FLT) and 3'-deoxy-2',3'-didehydrothymidine (D4T), nucleoside analogs shown to have potent activity against human immunodeficiency virus type 1 in culture (1-5, 10-12, 15, 16). Structurally, these compounds are quite similar to 3'-azido-3'-deoxythymidine (AZT; zidovudine), the only antiviral agent currently approved for the treatment of AIDS. The purpose of the present investigation was to characterize the dispositions of FDT and D4T in an animal model, the rat.Adult male Sprague-Dawley rats (Charles River, Wilmington, Mass.) weighing 250 to 325 g were used for the study. External jugular vein cannulas were implanted under light ether anesthesia the day before the experiment, and the rats were fasted overnight. FDT and D4T were provided by the Developmental Therapeutic Branch, AIDS Program, National Institutes of Health, Rockville, Md. FDT or D4T, dissolved in physiologic saline (7 to 8 mg/ml), was administered intravenously at a dose of 25 mg/kg of body weight through the jugular vein cannula, and the rats were placed in a metabolism cage. Six rats were studied for each drug. Blood samples (0.3 ml) were collected at selected times from the cannula into heparinized tubes. Preliminary studies showed no adsorption of the nucleosides to the cannulas. Blood was replaced with normal saline. Blood samples were immediately centrifuged, and plasma was frozen at -20°C until analysis. Urine samples were collected at 6-h intervals for 24 h and frozen until analysis. Preliminary studies demonstrated the stability of the nucleosides in urine. No drug was detected in urine from the last sample collection interval; therefore, the total amount of unchanged nucleoside excreted in urine was determined.FDT and D4T concentrations in plasma and urine were * Corresponding author.determined by high-performance liquid chromatography (HPLC). D4T served as the internal standard for measuring FDT concentrations, and FDT was used as the internal standard for determining D4T concentrations. To measure nucleoside concentrations in plasma, 100 ,I of plasma sample, 50 RI of internal standard (20 jxg/ml), and 100 ,ul of 2 M perchloric acid as a protein precipitant were thoroughly mixed in poly...

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Pharmacokinetics and saturable renal tubular secretion of zidovudine in rats

Cited by 50 publications

References 19 publications

Pharmacokinetics of the anti-human immunodeficiency virus nucleoside analog stavudine in cynomolgus monkeys

Pharmacokinetics of the anti-human immunodeficiency virus nucleoside analog stavudine in cynomolgus monkeys

An Evaluation Method for Nonlinear Local Disposition in Rat Liver and Kidney

Pharmacokinetics of 3'-fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine in rats

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