Possible differential induction of phase 2 enzyme and antioxidant pathways by american ginseng, Panax quinquefolius.

Human immunodeficiency virus (HIV)-infected patients often take herbal medicines, which may interact with antiretrovirals. American ginseng induces phase 2 and antioxidant enzymes in vitro and might increase the clearance of zidovudine and/or enhance antioxidant activity. Ten healthy volunteers received 300 mg of zidovudine orally before and after 2 weeks of treatment with a ginsenoside-enriched American ginseng extract 200 mg twice daily. This ginseng extract induced the phase 2 enzyme quinone reductase with an average concentration of doubling of enzyme activity of 190 microg/mL. Total ginsenoside content was 8.5 +/- 0.5%. Pharmacokinetic profiles of zidovudine and oxidative stress marker concentrations were measured post-zidovudine dose. American ginseng does not significantly affect the formation clearance of zidovudine to its glucuronide (ratio post- to pre-American ginseng = 1.17; 90% confidence interval: 0.95-1.45; P = .21), total clearance (ratio = 0.97; 0.82-1.14; P = .70), or plasma zidovudine AUC0-8 (ratio = 1.03; 0.87-1.21; P = .77). Oxidative stress biomarkers are reduced post-American ginseng (F2-isoprostane ratio = 0.79; 0.72-0.86; P < .001; 8-hydroxy-deoxyguanosine ratio = 0.74; 0.59-0.92; P = .02). Two weeks of American ginseng does not alter zidovudine pharmacokinetics but reduces oxidative stress markers.

Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS-related complex.

The anti-human immunodeficiency virus drug zidovudine is metabolized extensively in human beings to the 5'-glucuronide (GAZT) and is cleared rapidly, resulting in a short half-life and the need for frequent dosing. This study explores whether probenecid, which is also metabolized by glucuronidation, reduces zidovudine clearance when zidovudine is administered orally to patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). The mean zidovudine plasma levels were significantly higher after concurrent administration of probenecid than in its absence, resulting in a twofold increase in the mean AUC, a corresponding decline in the apparent total clearance, and a prolongation in the mean half-life. Similar alterations were observed in GAZT disposition. There was a marked reduction in the urinary excretion ratio of GAZT to zidovudine and a decline in the renal clearance of GAZT after probenecid coadministration. Probenecid inhibits zidovudine glucuronidation and renal excretion of GAZT.

Pharmacokinetics of zidovudine (azidothymidine). II. Development of metabolic and renal clearance pathways in the neonate.

The pharmacokinetics of zidovudine (ZDV or azidothymidine) were investigated in newborn macaques (Macaca nemestrina) at various ages ranging from less than 1 week to 4 months. The mean ZDV total plasma clearance, renal clearance, and the metabolic clearance of ZDV to the glucuronide (ZDVG) were significantly (p less than 0.05) smaller during the first week of life (6.15 +/- 1.03, 4.25 +/- 0.36, and 1.19 +/- 0.67 ml/min/kg, respectively) than the corresponding estimates at the age of 4 months (19.62 +/- 3.5, 8.28 +/- 1.90, and 8.28 +/- 2.24 ml/min/kg, respectively). The mean estimates of these parameters at 4 months were close to those found in adult macaques (23.55 +/- 1.48, 10.05 +/- 0.75, and 10.5 +/- 1.9 ml/min/kg, respectively), indicating that these clearance pathways develop rapidly, within 4 months of birth. If similar results are obtained in human neonates, therapeutic drug monitoring should be instituted when administering ZDV to this population so that the dose of ZDV may be adjusted to correspond with age-related changes in total plasma clearance of ZDV.

Compliance with zidovudine therapy in patients infected with human immunodeficiency virus, type 1: a cross-sectional study in a municipal hospital clinic.

PURPOSE: To determine the extent of and clinical variables associated with zidovudine compliance. PATIENTS AND METHODS: A survey of 83 patients infected with human immunodeficiency virus (HIV) followed in a municipal hospital clinic was performed. Compliance histories were validated by serum and urine zidovudine levels. Patient characteristics included 46% white, 63% with a history of intravenous drug use, and 59% reporting a diagnosis of acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). The main outcome measure was greater than 80% compliance with prescribed doses of zidovudine over the previous week. RESULTS: Sixty-seven percent of the study patients reported greater than 80% compliance with prescribed doses of zidovudine over the previous week. The most common explanations given for missing a dose were "forgot to take zidovudine" and "did not have the medication with me." Five variables were independently associated with greater than 80% compliance as determined by stepwise multiple logistic regression: patient belief that zidovudine prolongs life (odds ratio [OR] 9.3, [95% confidence interval (CI) 2.4, 36.7]), a diagnosis of AIDS or ARC (OR 5.5, [CI 1.5, 20.4]), use of a medication timer (OR 4.4, [CI 1.0, 19.1]), no history of intravenous drug use (OR 3.7, [CI 1.0, 14.2]), and taking one to three other medications with zidovudine. CONCLUSIONS: High compliance with zidovudine was achieved by HIV-infected patients in a municipal hospital clinic, many of whom had a history of intravenous drug use. Compliance with zidovudine may be enhanced by a patient's belief that it prolongs life and the use of a medication timer for proper dosing.

Modulation of 3'-azido-3'-deoxythymidine catabolism by probenecid and acetaminophen in freshly isolated rat hepatocytes.

Metabolic studies of 3'-azido-3'-deoxythymidine (AZT) in humans have demonstrated that this compound is primarily eliminated as a 5'-O-glucuronide, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GAZT), accounting for approximately 80% of the administered dose. Recently, we characterized the complete catabolic pathway of AZT in freshly isolated rat hepatocytes in suspension, demonstrating extensive formation of three catabolites, including GAZT, 3'-amino-3'-deoxythymidine (AMT), and 3'-amino-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GAMT). The present study evaluated the effects of probenecid (PROB) and acetaminophen (ACET), two agents which are also metabolized by UDP-glucuronyltransferase, on the metabolism and transmembrane distribution of AZT in rat hepatocytes. Pre-exposure of cells to 350 microM PROB 30 min prior to the addition of 10 microM [3H]AZT decreased intracellular GAZT levels by approximately 10-fold. Interestingly, AMT formation was enhanced approximately 1.5-fold in the presence of PROB, probably resulting from increased AZT availability. In contract, pre-exposure to 50 microM ACET 30 min prior to addition of 10 microM [3H]AZT did not substantially alter AZT glucuronidation. Additionally, decreased AZT catabolism by PROB did not contribute to the formation of 5'-phosphorylated derivatives of AZT. Agents which undergo glucuronidation may thus not necessarily affect AZT conversion to GAZT, and their potential interactions should be investigated using in vitro systems prior to co-administration with AZT.

Zidovudine pharmacokinetics in HIV-positive women during different phases of the menstrual cycle.

STUDY OBJECTIVE: To examine the pharmacokinetics of zidovudine during the menstrual cycle in human immunodeficiency virus- (HIV-) positive women. DESIGN: Open, unblinded study. SETTING: A women's clinic for acquired immunodeficiency syndrome (AIDS) at a large medical center. PATIENTS: HIV-positive women with a CD4+ cell count above 200/mm3, receiving long-term zidovudine therapy, with a history of regular menstrual cycles. INTERVENTIONS: All patients received a 100-mg dose of zidovudine in the fasted state on three occasions. MEASUREMENTS AND MAIN RESULTS: Zidovudine and zidovudine-glucuronide plasma concentrations were measured with radioimmunoassay to determine the pharmacokinetic characteristics during each menstrual phase. The drug's mean peak plasma concentrations (range 233-808 ng/ml) were 556 +/- 145, 385 +/- 132, and 495 +/- 143 ng/ml during the menstrual, late follicular-ovulatory, and luteal phases, respectively. Initially, plasma concentrations declined in a linear fashion from 0 to 4 hours, with a prolonged elimination phase in many patients after 4 hours. The mean zidovudine area under the curve was 886 +/- 156, 845 +/- 268, and 775 +/- 167 ng.hour/ml. The mean percentage of dose recovered was 44.2 +/- 26.0, 56.9 +/- 19.1, and 42.2 +/- 16.6, respectively. CONCLUSIONS: The pharmacokinetics of zidovudine were not different during the three phases of the menstrual cycle; however, considerable intrapatient and interpatient variability was noted for many of the values.

Zidovudine pharmacokinetics in five HIV seronegative patients undergoing continuous ambulatory peritoneal dialysis.

A few reports in the literature describe zidovudine (AZT) pharmacokinetics in patients undergoing hemodialysis; however, the effect of continuous ambulatory peritoneal dialysis (CAPD) on the drug's disposition has not been studied. The pharmacokinetics of AZT were evaluated in five patients, age 37-62 years, who were seronegative for the human immunodeficiency virus and were undergoing CAPD. Serial plasma, urine, and dialysate samples were collected after oral administration of AZT 200 mg. Samples were assayed using radioimmunoassay (RIA). Model-independent analysis was used to determine total plasma clearance, apparent volume of distribution, mean residence time, and half-life. Net peritoneal dialysis clearance was calculated to measure the effect of CAPD on AZT disposition. We found wide interpatient variability in AZT pharmacokinetics. Peak serum concentrations ranged from 0.3-47.8 microns and area under the curve from 0.5-26.1 mg x hour/L. These differences resulted in corresponding differences in clearance (range 66-3176 ml/min/1.73 m2) and volume of distribution (range 16-825 L). Interpatient variability in glucuronidation may partially account for this variability. Net peritoneal dialysis clearance of AZT was 5 ml/minute. Although the effect of peritoneal dialysis on AZT disposition was negligible, clinicians should be aware of the large differences in the way in which individual patients with renal dysfunction handle this drug.

Effect of probenecid on the renal and nonrenal clearances of zidovudine and its distribution into cerebrospinal fluid in the rabbit.

The effect of probenecid on the renal excretion of zidovudine (3'-azido-3'-deoxythymidine; AZT) and its distribution into CSF was studied in the rabbit. Although probenecid is chemically unrelated to AZT, it has been shown that probenecid inhibits AZT elimination in Acquired Immunodeficiency Syndrome (AIDS) patients. The effect of probenecid on the renal clearance of AZT after an iv bolus dose was studied in crossover experiments in the absence (control) and the presence of a continuous iv infusion of probenecid. Probenecid coadministration increased the AZT plasma AUC by 70%, by proportionally decreasing the total body clearance. The renal clearance decreased by 50%. The effect of probenecid on the renal clearance of AZT at steady state was studied by measuring the renal clearance of AZT at different steady-state plasma probenecid concentrations. The renal clearance of AZT decreased with increasing probenecid concentration, suggesting competitive inhibition of the secretion of AZT in the renal tubule. The relationship between AZT renal clearance and probenecid plasma concentrations, during and after probenecid iv infusion in conscious and in anesthetized uretercannulated rabbits, showed hysteresis, indicating that probenecid plasma concentration is different from the concentration at the site of interaction. This suggests the presence of an effect compartment for the inhibition of AZT renal excretion by probenecid. The effect of probenecid on the CSF distribution of AZT was also studied in the rabbit. Probenecid coadministration caused a sevenfold increase in the AZT AUCCSF in probenecid-treated rabbits when compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of accelerator mass spectrometry to measure the pharmacokinetics and peripheral blood mononuclear cell concentrations of zidovudine.

The remarkable sensitivity of accelerator mass spectrometry (AMS) is finding many new applications in pharmacology. In this study AMS was used to measure [(14)C]-Zidovudine (ZDV) concentrations at the drug's site of action (peripheral blood mononuclear cells, PBMCs) following a dose of 520 ng (less than one-millionth of the standard daily dose) to a healthy volunteer. In addition, the pharmacokinetics of this microdose were determined and compared to previously published parameters for therapeutic doses. Microdose ZDV pharmacokinetic parameters fell within reported 95% confidence intervals or standard deviations of most previously published values for therapeutic doses. Blood, urine, stool, saliva, and isolated PBMCs were collected periodically through 96 h postdose and analyzed for ZDV and metabolite concentrations. The results showed that ZDV is rapidly absorbed and eliminated, has one major metabolite, and is sequestered in PBMCs. (14)C mass balance assessments indicated a significant portion of ZDV remained after 96 h with a much prolonged elimination half-life. Results of this study demonstrate the usefulness of microdosing and AMS as a tool for studying the pharmacokinetic characteristics, including PBMC concentrations, of ZDV and underscore the value of AMS as a tool with which to perform pharmacokinetic and mass balance studies using trace amounts of radiolabeled compound.

Quantification of zidovudine and one of its metabolites in plasma and urine by solid-phase extraction and high-performance liquid chromatography.

A rapid, sensitive and selective method for the quantification of zidovudine (AZT) and one of its metabolites (the 5'-glucuronyl form of zidovudine, G-AZT) in biological fluids is described, based on high-performance liquid chromatography. Solid-phase extraction on-line with chromatographic separation was used. The limit of quantitation of the assay is 10 ng/ml of plasma or urine for G-AZT and 20 ng/ml of plasma or urine for AZT.

Probenecid inhibits the metabolic and renal clearances of zidovudine (AZT) in human volunteers.

The effect of probenecid on the disposition of AZT was investigated in a pilot study in two healthy volunteers. The pharmacokinetics of AZT were examined after a single oral dose of 200 mg with and without probenecid coadministration in a balanced crossover study. Administration of 500 mg probenecid every 6 hr prior to and during AZT dosing resulted in an increase in the average AUCAZT from 89 micrograms.min/ml (control) to 191 micrograms.min/ml during probenecid treatment. This was manifested by a corresponding decrease in CLTOT/F, which is attributed to the inhibitory effect of probenecid on the glucuronidation and renal excretion of AZT. Average CLR and CLTOT/F of AZT decreased from 4.76 and 28.7 to 2.98 and 14.1 ml/min/kg during control and probenecid treatment, respectively. AZT glucuronidation was affected to a greater extent than its renal excretion, as reflected by the decreased ratio of GAZT/AZT urinary recoveries. The terminal half-life of AZT was slightly longer during probenecid administration. That only a small change in the half-life occurred indicates that probenecid also reduced the volume of distribution of AZT. The CLR of GAZT decreased from an average of 11.3 ml/min/kg (control) to 2.63 ml/min/kg during probenecid treatment, resulting in a greater than 3.5-fold increase in AUCGAZT. Probenecid did not affect the blood/plasma distribution or the plasma protein binding of AZT. These preliminary findings suggest that it may be possible to maintain effective plasma AZT concentrations in AIDS patients receiving a reduced daily dose, in combination with probenecid.

Simple and effective procedure for complete urine collection from infant macaques (Macaca nemestrina).

A diaper method, used in pediatric medicine, has been adapted and validated for total urine collection from infant macaques (Macaca nemestrina). The device consists of cellulose sponges and polyethylene sheets. The method proposed is non-invasive, simple, and does not significantly hinder the movement of the infant. The method should be useful when one is conducting pharmacokinetic studies in which total urine collection is required.

Pharmacokinetic evaluation of drug interactions with anti-human immunodeficiency virus drugs. VI. Effect of the calcium channel blocker nimodipine on zidovudine kinetics in monkeys.

Coadministration of zidovudine (AZT) and nimodipine, a calcium-channel blocker, is a potential therapeutic regimen in acquired immunodeficiency syndrome patients based on the report that nimodipine can prevent human immunodeficiency virus-induced neurotoxicity in vitro. An evaluation of the pharmacokinetics of AZT and its glucuronide metabolite 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranurosylthymidine (GAZT) in the presence and absence of nimodipine in monkeys was undertaken. After 20 mg/kg of AZT given i.v. in the presence and absence of nimodipine, nimodipine caused a significant reduction (41%) in the volume of distribution of AZT at steady state and a 22% decrease in total clearance. The disposition of GAZT was also influenced by nimodipine, causing a large increase in its area under the plasma concentration-time curve. Renal excretion data for AZT and GAZT, although inconclusive, suggested nimodipine caused a decrease in the renal clearance of AZT with a minimal change in the renal clearance of GAZT. The combined effects of nimodipine on the clearance of AZT and volume of distribution at steady state produced no change in its elimination half-life.

Effect of rifabutin on the pharmacokinetics of zidovudine in patients infected with human immunodeficiency virus.

We investigated the effects of rifabutin (300 mg daily administered for 7 or 14 days) on the pharmacokinetics of zidovudine in nine patients who were infected with human immunodeficiency virus (HIV). Serial blood and urine samples were collected over a 6-hour period on each day that the pharmacokinetics of zidovudine were studied. Pharmacokinetic parameters were determined for zidovudine and its glucuronide metabolite and compared with use of analysis of variance (ANOVA) appropriate for a repeated-measures design. Except for a statistically significant decrease (28%) in the terminal half-life of zidovudine from 1.5 to 1.1 hours (P = .005) after coadministration of both agents for 14 days, concurrent administration of rifabutin for 7 or 14 days had no statistically significant effects on zidovudine plasma and urine pharmacokinetic parameters (the difference among treatment means was < 25%). Treatment with rifabutin is unlikely to influence the effectiveness of treating HIV-infected patients with zidovudine because of any pharmacokinetic interaction between these drugs.

Trimethoprim, alone or in combination with sulphamethoxazole, decreases the renal excretion of zidovudine and its glucuronide.

Trimethoprim and trimethoprim-sulphamethoxazole (co-trimoxazole) are often prescribed in HIV patients treated with zidovudine. The pharmacokinetics of zidovudine, after a dose of 3 mg kg-1 by constant rate intravenous infusion over 1 h were evaluated in nine HIV patients in an open, randomized, three-phase crossover study, without and with trimethoprim (150 mg) and trimethoprim-sulphamethoxazole (160 and 800 mg). The metabolic clearance of zidovudine was not significantly influenced by trimethoprim-sulphamethoxazole and trimethoprim. However, the renal clearance of zidovudine was decreased by 58 and 48%, respectively, and that of its glucuronide by 27 and 20% (P < 0.05). The fraction of the dose excreted as the parent compound fell by 47 and 39% and the metabolic ratio by 48 and 43% (P < 0.05). This kinetic drug interaction, apparently due solely to trimethoprim, may only be clinically important when hepatic glucuronidation is also impaired by liver disease or inhibited by other drugs.

Tissue distribution and metabolic disposition of zidovudine in rats.

The tissue distribution and metabolic fate of [5'-3H]zidovudine was studied in rats after a single dose of 10 mg/kg by gavage. The drug was absorbed rapidly and distributed into all tissues. Peak blood and tissue levels were observed 0.25 hr post-dose. The level of peak radioactivity in the stomach, intestine, liver, spleen, adrenals, and kidney was higher than in plasma, while in the heart, lung, thymus, lymph nodes, muscle, bone, and skin it was similar to that in plasma. Only in the testes and the brain the radioactivity was lower than in plasma. Blood and plasma radioactivity levels were nearly equivalent. A biphasic disappearance of radioactive material was observed in blood and plasma, as well as in most tissues, with a rapid decline in the early phase (0.25-4 hr) and a slower decline thereafter. The 0-24-hr urinary and fecal recoveries (mean +/- SD) of radioactive material were 78 +/- 14% and 20 +/- 9% of dose, respectively, indicating virtually complete recovery of the radioactive dose. Reversed-phase HPLC analysis indicated that approximately 88% of urinary radioactivity corresponded to unchanged zidovudine, with the remaining radioactivity accounted for by five metabolites. One of these urinary metabolites was identified as 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine and another as 3'-amino-3'-deoxythymidine (AMT). The majority of fecal radioactivity (greater than 70%) corresponded to AMT. There is a component of biliary excretion in the disposition of zidovudine. At least 7% of a parenteral dose of zidovudine was secreted in the bile, primarily as 3'-azido-3'-deoxy-5'-beta-D-glucuronylazidothymidine, which may be a source of fecal AMT.

Simultaneous analysis of azidothymidine and its mono-, di- and triphosphate derivatives in biological fluids, tissue and cultured cells by a rapid high-performance liquid chromatographic method.

A rapid high-performance liquid chromatographic (HPLC) method for the simultaneous analysis of the antiviral drug azidothymidine (AZT), AZT monophosphate, AZT diphosphate and AZT triphosphate, with ultraviolet detection in the nanomolar range, is described. Determination of these compounds in vitro in the human MT-4 lymphocyte cell line did not require a prior extraction, and AZT and its phosphorylated derivatives could be accurately analysed in one HPLC run. However, plasma, bile, liver homogenate and urine samples could not be injected directly into the chromatograph. Therefore, a solid-phase extraction procedure was developed, using azidodideoxyinosine as internal standard. The extractions of the compounds of interest from all but urine samples were reproducible, with recoveries between 65% (AZT triphosphate from plasma) and 100% (AZT from plasma).

Pharmacokinetics of simultaneously administered zidovudine and didanosine in HIV-seropositive male patients.

Our objective was to determine whether a pharmacokinetic interaction exists between zidovudine and didanosine when they are coadministered. This was designed as a randomized, three-period, three-treatment, six-sequence, crossover study with a 1-week washout period between treatments. The patients were six men infected with human immunodeficiency virus who were asymptomatic. On three separate occasions, patients received zidovudine alone (200 mg every 8 h) for 3 days, didanosine alone (200 mg every 12 h) for 3 days, or zidovudine and didanosine for 3 days. On the fourth day, each patient received the final dose of each regimen, and blood and urine were serially collected for 8 h. Pharmacokinetic parameters were assessed for zidovudine, its glucuronide metabolite (GZDV), and didanosine. Coadministration of zidovudine had no significant effect on didanosine pharmacokinetic parameters (< 12% difference between treatment means, p > 0.1). Coadministration of didanosine did not significantly alter zidovudine pharmacokinetic parameters but did cause statistically significant increases in the renal and apparent formation clearances of GZDV (18.5% and 30.5% difference between the treatment means, respectively, p < 0.025). Therapeutic doses of zidovudine did not alter didanosine pharmacokinetic parameters. Coadministration of didanosine did not affect zidovudine parameters but did cause small alterations in GZDV pharmacokinetic values. These changes are unlikely to be clinically significant.

Porous graphitic carbon shows promise for the rapid chromatographic analysis of polar drug metabolites.

A rapid and simple HPLC method has been developed and used to separate the polar metabolic conjugates of AZT, chloramphenicol, and beta-estradiol based upon the use of porous graphitic carbon. The HPLC system is sufficiently selective to resolve the polar drug conjugates from their parent compounds and from endogenous material present in urine. The compounds are separated, without the need for sample pretreatment or gradient elution, on a porous graphitic carbon (Hypercarb) column using aqueous trifluoroacetic acid modified with tetrahydrofuran as the mobile phase. Porous graphitic carbon exhibits a novel mechanism of retention towards these very polar substances, which are unretained under reversed-phase conditions on alkyl-bonded silica phases.