Interactions among drugs for HIV and opportunistic infections.
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AIDS-Related Opportunistic Infections↗
Biomedical subjects
K D Gallicano
Publications and source records attributed to K D Gallicano.
Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients.
AIMS: The objective of the study was to determine the effect of multiple doses of rifampicin on the steady-state pharmacokinetics of zidovudine and its 5'-glucuronosyl (GZDV) and 3'-amino (AMT) metabolites. METHODS: Eight asymptomatic HIV-infected patients (seven male, one female) participated in this three-period longitudinal study. Each patient received zidovudine (200 mg every 8 h) for 14 days (period 1), followed by rifampicin (600 mg every 24 h) with zidovudine for 14 days (period 2), and then zidovudine alone for a further 14 days (period 3). Blood and urine samples were collected over 6 h on the last day of each period for measurements of zidovudine and GZDV by h.p.l.c.-u.v. and AMT by h.p.l.c.-m.s-m.s. RESULTS: Compared with zidovudine-alone values in period 1, 14 days of coadministration with rifampicin significantly increased zidovudine oral clearance (89%) and formation clearances to GZDV (100%) and AMT (82%). Correspondingly, there were decreases in maximum plasma concentration (43%), AUC (47%) and urine recovery (37%) of zidovudine. GZDV/zidovudine and AMT/zidovudine AUC ratios increased by 99% and 36%, respectively, despite a significant 29% decrease in AMT AUC. After stopping rifampicin for 14 days, values of these pharmacokinetic parameters returned to within 26% of baseline. Over the three periods AMT plasma levels were <18 ng ml-1 (n=6) and <40 ng ml-1 (n=2), and molar AMT/zidovudine AUC ratios ranged from 1.7% to 4.5%. CONCLUSIONS: Rifampicin induced zidovudine glucuronidation and amination pathways resulting in decreased plasma and urine exposures to zidovudine. AMT plasma exposure decreased because induction was more pronounced for the major GZDV metabolite. The magnitude of the residual inductive effect was minimal at 14 days after stopping rifampicin.
Adult↗
Effect of ciprofloxacin on the disposition of 14C-dideoxyinosine-derived radioactivity in the rat.
The potential for the antibacterial agent ciprofloxacin to interfere with the disposition of the antiviral agent dideoxyinosine (ddI) was evaluated in adult male Wistar rats. The combination group (n = 10) was dosed orally with 100 mg/kg ciprofloxacin in water every 12 h for three consecutive doses. Thirty minutes after the last dose, a bolus IV injection of 50 mg/kg 14C-ddI in physiologic saline was given over 7-10 sec through the penile vein. The control group (n = 8) received a single dose of IV 14C-ddI. Blood, urine and fecal samples were collected from 0-4 h, and tissue samples were removed at 4 h after ddI administration. The disappearance of 14C from blood followed the kinetics of a two-compartment model with bolus input and first-order output. The following pharmacokinetic parameters (mean +/- SD) were calculated based on total blood radioactivity for the 14C-ddI alone and combination groups, respectively: blood clearance 13.5 +/- 2.0 vs. 12.7 +/- 1.5 ml/min/kg, terminal disposition half-life 49.9 +/- 2.2 vs. 49.0 +/- 6.0 min, steady-state volume of distribution 891 +/- 134 vs. 825 +/- 126 ml/kg, mean residence time 66.2 +/- 3.1 vs. 65.0 +/- 7.8 min (the power to detect a 20% decrease in the above parameters, relative to the reference ddI alone, was > 85% at the 5% significance level), percentage of administered dose recovered in urine 62.2 +/- 9.8% vs. 56.6 +/- 13.0%. Most of the radioactivity in tissues was concentrated in the liver, adrenal, spleen and kidney. Except for significant decreases (p < 0.05) in the levels of 14C in skeletal muscle and cecum of combination treated rats, the coadministration of ciprofloxacin showed no differences in either the tissue levels of 14C or the pharmacokinetic parameters of 14C-ddI-derived radioactivity. The results obtained with total 14C measurements suggest that ciprofloxacin does not alter the disposition of ddI in the rat, although unchanged ddI was not determined.
Administration, Oral↗
Pharmacokinetics of single and chronic dose zidovudine in two HIV positive patients undergoing continuous ambulatory peritoneal dialysis (CAPD).
The effect of continuous ambulatory peritoneal dialysis (CAPD) on zidovudine (ZDV) elimination was studied in two HIV-positive men. Serum and dialysate samples were collected after a single oral dose of 200 mg (patient 1) or 100 mg (patient 2) of ZDV, and again on at least one occasion during chronic therapy (100 mg every 8 h). Concentrations of ZDV and its glucuronide metabolite (GZDV) were measured by radioimmunoassay. ZDV serum half-lives on day 1 were 7.9 h (patient 1) and 2.6 h (patient 2). The apparent GZDV half-lives on day 1 were 19.9 h (patient 1) and 7.1 h (patient 2), with resultant accumulation of metabolite (up to 36 micrograms/ml) during chronic therapy. At 14 h following single dose, 8.2 +/- 0.4% of dose was recovered in dialysate as GZDV; ZDV accounted for less than 0.6% of dose recovered in dialysate after both single and multiple dose. After the initial dwell (tau) following single dose, peritoneal clearances of ZDV were 4.3 ml/min (tau = 4 h, patient 1) and 5.9 ml/min (tau = 5 h, patient 2), and GZDV clearances were 6.7 and 5.1 ml/min, respectively. ZDV serum protein binding was less than 10%. The small amount of unchanged ZDV removed by CAPD suggests that no supplemental doses are needed in HIV patients undergoing CAPD.
Acquired Immunodeficiency Syndrome↗
Isolation of cross-reacting compounds to Incstar Cyclo-Trac SP RIA in blood samples obtained from cardiac allograft patients on cyclosporine therapy.
To examine the specificity of the Incstar Cyclo-Trac SP RIA kit, individual blood samples from 28 cardiac allograft patients on cyclosporine A (CsA) therapy were extracted and chromatographed by HPLC. Initially, eluates from a pool of the above samples were collected at regular intervals and measured by RIA to locate possible cross-reacting compounds. Unknown cross-reacting materials were detected in a fraction (UNK) that was collected before elution of CsA. For each patient's sample, fraction UNK and the fraction containing CsA were then collected and measured by RIA. In 9 of 28 samples, cross-reactivity was detected in fraction UNK; range 11 to 36%, mean 22 +/- 7.5%. Cross-reactivity was not apparent in fraction UNK of CsA-free blood samples from normal volunteers.
Antibody Specificity↗
Monitoring of blood levels of cyclosporine in renal and cardiac transplant recipients--comparison of HPLC to Incstar CYCLO-Trac SP RIA.
Cyclosporine in whole blood samples from renal and cardiac transplant recipients was measured by high-performance liquid chromatography (HPLC) and by CYCLO-Trac SP specific radioimmunoassay (RIA). The fresh samples assayed by RIA were remeasured in a second laboratory after storage at -20 degrees C for two to six months and good interlaboratory agreement was obtained on the 59 samples assayed (y = 0.926x + 14.8 micrograms/L, r = 0.982). The calibration curve for RIA was not influenced by fresh whole blood, hemolyzed whole blood or serum matrix from normal volunteers. However, comparison of the RIA results from patient samples with those from an HPLC procedure showed that RIA values averaged about double those measured by HPLC. The difference is attributable to differences between the blood matrix of transplant and nontransplant subjects, rather than exclusively to the apparent nonspecific nature of the antibody.
Calibration↗
Situation paper: comparative bioavailability of oral contraceptive products. Developed from a workshop in Ottawa, June 4, 1990.
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Biological Availability↗
Interchangeability of low-dose oral contraceptives. Are current bioequivalence testing measures adequate to ensure therapeutic equivalency?
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Biological Availability↗
Dextran sulfate disposition in the rat.
Comparative studies of oral and intravenous administration of tritiated dextran sulfate in rats showed markedly different distribution patterns. Following IV dosing about 50 per cent of the radioactivity was recovered in feces and urine within 24 h. The major portion of the recoverable dose was eliminated in the urine as dextran sulfate within 3 h after administration. In orally treated rats only about 32 per cent of the 3H was recovered in the feces and urine, the major fraction being associated with unabsorbed dextran sulfate in the feces. The remainder of the dose in both treatment groups has apparently distributed throughout the rat body with some accumulation in the liver, kidney and spleen. Consequently, the disposition of about 67 per cent or the oral dose could not be fully accounted for by these excretion routes. However, separation with Sephadex columns showed similarities in the 24 h plasma and urine profiles of the IV and orally dosed rats which suggest that while the oral dose was absorbed as dextran sulfate, it underwent rapid metabolism to small molecular weight products prior to entering the systemic circulation which were then widely distributed within the rat.
Administration, Oral↗
Identification of metabolites of methylprednisolone in equine urine.
Methylprednisolone and three metabolites, 17,21-dihydroxy-6 alpha-methyl-1,4-pregnadiene-3,11,20-trione, 6 alpha-methyl-17,20 beta,21-trihydroxy-1,4-pregnadiene-3,11-dione, and 6 alpha-methyl-11 beta,17,20 beta,21-tetrahydroxy-1,4-pregnadien-3-one were detected in equine urine after intraarticular administration of methylprednisolone acetate. All four compounds were excreted both in the unconjugated form and as glucuronic acid conjugates. They were identified by comparing data obtained from analyses by high performance liquid chromatography, thin-layer chromatography, ultraviolet spectroscopy and gas chromatography/mass spectrometry to those of the synthesized standards. The presence of trace amounts of a fourth metabolite, 6 alpha-methyl-11 beta,17,20 alpha,21-tetrahydroxy-1,4-pregnadien-3-one, was indicated by high performance liquid chromatography but confirmation has not been attained by the other methods.
Animals↗
A sensitive liquid chromatographic procedure for the analysis of camphor in equine urine and plasma.
A sensitive method was required to analyze low levels of camphor in equine urine and plasma. Camphorated oil (20% w/w camphor) was administered topically (6 g) and intratracheally (1 g) to standardbred mares. The drug was extracted from urine and plasma by diethyl ether and analyzed as its 2,4-dinitrophenylhydrazone derivative by reverse phase HPLC with UV detection. The UV detector was set at 368.5 nm and the samples were eluted from the C18 column by 82% acetonitrile in water. The detection limit achieved was about 10 ng/mL urine and about 20 ng/mL plasma. After topical administration, only trace amounts of camphor were found in urine, whereas in plasma detectable quantities appeared from 20 min to 12 hrs post-administration. After intratracheal administration, camphor appeared immediately in both urine and plasma and occurred in higher concentrations. The concentrations of camphor ranged from 11.4 to 21.6 ng/mL urine during 2 hrs post-administration and from 46.7 to 1650 ng/mL plasma during 1 hr. All traces of camphor disappeared from urine after 4 hrs and from plasma after 12 hrs. A GC/MS analysis of hydrolyzed urine extracts indicated two metabolites of camphor: trans-isoketopinic acid and an as yet uncharacterized hydroxycamphor.
Animals↗
An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic.
PURPOSE: Garlic has been used as a flavouring agent, traditional medicine, and functional food to improve physical or mental well-being. Garlic and garlic products generally have been regarded as safe but a number of conflicting reports in the literature and confounding factors make it difficult to unequivocally establish the clinical efficacy and safety of these products either alone or in the presence of therapeutic products. A preliminary study was undertaken with fresh garlic and garlic products using the major cDNA-expressed human cytochrome P-450 isozymes associated with the metabolism of HIV/AIDS drugs, and purified P-glycoprotein (P-gp) cell membranes to ascertain the risk potential for generating interactions with therapeutic products. METHODS: A broad screening was undertaken with 10 garlic products (aged, odourless, oil, freeze-dried) and 3 varieties of fresh garlic bulbs (common, Elephant and Chinese), all purchased from local outlets, to examine their potential to affect human cytochrome P-450 2C9*1, 2C9*2, 2C19, 2D6, 3A4, 3A5 and 3A7 mediated-metabolism of marker substrates using an in vitro fluorometric microtiter plate assay. Four garlic products were screened for their potential to interact with P-gp using an in vitro colourmetric ATPase assay. RESULTS: Extracts of fresh garlic, different brands and lots of odourless garlic and representative samples of garlic oil, freeze dried garlic, and aged garlic exhibited an inhibitory effect on cytochrome P450 2C9*1, 2C19, 3A4, 3A5 and 3A7 mediated metabolism of a marker substrate. The activity of 2D6 mediated-metabolism was generally unaffected by garlic. Extracts of the fresh garlic stimulated CYP2C9*2 metabolism of the marker substrate. With the extracts tested, garlic had very low to moderate P-gp interaction as compared with the positive control verapamil. CONCLUSIONS: Our in vitro findings demonstrate that garlic components can affect cytochrome P-450 2C, 2D and 3A mediated-metabolism of the isoforms studied. The safety and efficacy of conventional therapeutic products metabolized by the affected isozymes, particularly those with a narrow therapeutic index, taken concomitantly with garlic needs to be examined further under clinical settings.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Simultaneous liquid chromatographic screening of five coccidiostats in chicken liver.
A reverse-phase liquid chromatographic (LC) method is described for simultaneously determining 5 coccidiostats--aklomide, dinsed, ethopabate, nitromide, and zoalene in chicken liver. The method entails blender extraction of 10 g liver with ethyl acetate, column chromatography through Sephadex LH-20 and neutral alumina, and LC analysis on a C18 column with UV detection at 260 nm. The drugs were eluted from Sephadex with methanol-benzene (10 + 90), from alumina with methanol-dichloromethane (10 + 90), and from C18 with acetonitrile-water (linear gradient: 25% acetonitrile for 10 min, increasing to 55% over 15 min; flow rate 1 mL/min). Liquid chromatography was completed in 40 min and calculations were based on peak height measurements. Average recoveries of the coccidiostats from fortified liver ranged from 72 to 97%, except for dinsed, which showed a relatively constant average recovery of 57%. The detection limit for the standards was 2.5 ng on column. Levels as low as 50 ng/g were detected in fortified liver samples.
Animals↗