Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Probenecid”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,369 records · Page 76Linked to original sources

Penetration of ampicillin into urethral and cervical secretions after oral administration of bacampicillin.

The study comprised 24 male and 24 female patients treated either for uncomplicated gonorrhoea or as a prophylaxis. A single dose of 800 mg of bacampicillin + 1.0 g probenecid was administered orally to each patient. The concentrations of ampicillin in urethra and cervix were assayed by means of alginate swabs that were used as diffusion centres on agar diffusion plates. The inhibition zones were compared with a standard series of swabs containing known amounts of ampicillin. The amounts of secretions absorbed into the swabs were determined by weighing each swab before and after taking the specimen. The median ampicillin concentration in the male urethra one hour after the single dose of bacampicillin plus probenecid was 2.0 micrograms/ml of urethral secretion and increased to 3.2 micrograms/ml two hours after administration of the antibiotic. In the female urethra, the median concentrations of ampicillin were 1.5 micrograms/ml and 2.3 micrograms/ml of urethral secretion one and two hours, respectively, after the same dosage as above. The corresponding ampicillin concentrations in the cervical secretion were 1.6 micrograms/ml and 2.9 micrograms/ml, respectively.

Administration, Oral↗

Uricosuric effect of irtemazole in healthy subjects.

Following a single dose of 50 mg irtemazole per os, plasma uric acid levels decreased after 1 h and fell to 53.5% of the original value within 6-12 h. Renal uric acid excretion increased up to 66 mg/h 30 min after drug application and reached its maximum of 151 mg/h 30 min later. Uric acid clearance also increased after 30 min and reached its maximum of 56 ml/min after 60 min. The response of the kidney to irtemazole is faster than to benzbromarone or probenecid. Lowering of plasma uric acid has a shorter-lasting effect than benzbromarone or probenecid. At 24 h after the application of 50 mg irtemazole the decrease of the plasma uric acid was between 15.4% and 30.0%, or 24.7% on average. Three days after the application the basic plasma uric acid levels were reached again.

Administration, Oral↗

Favorable effect on postgraduate clinical practice of a drug-interaction exercise for undergraduate students.

AIM: Undergraduate students in Jichi Medical School participated in a laboratory exercise investigating the furosemide-probenecid interaction at the end of their clinical pharmacology (CP) course. The aim of this study was to determine whether they learned to recognize drug interactions better than students who did not take such a course. METHODS: We conducted a postal survey of physicians who had graduated from Jichi Medical School or from other medical schools without a CP course including the exercise. Questions were asked concerning: (1) the recognition of furosemide-probenecid and nine other drug interactions, and (2) the need to anticipate drug interactions and their adverse effects before writing prescriptions. RESULTS: The degree of the recognition of all drug interactions, and the percentage of physicians who responded that knowledge of drug interactions and adverse effects were essential before writing prescriptions, were significantly greater in physicians who had taken an undergraduate CP course than in those who had not. CONCLUSIONS: CP courses with specific laboratory exercises on drug interactions lead future physicians to recognize drug interactions and their adverse effects.

Drug Interactions↗

A simplified analysis of [18F]3'-deoxy-3'-fluorothymidine metabolism and retention.

PURPOSE: [18F]3'-deoxy-3'-fluorothymidine (FLT) is a thymidine analog developed for imaging tumor proliferation with positron emission tomography (PET). To quantitatively assess images, the blood activities of FLT and its glucuronidated metabolite were measured and its kinetics analyzed. This study sought to limit the number of blood samples needed to measure FLT retention. METHODS: Total FLT activity was measured from 18 venous samples obtained over the first hour and dynamic imaging performed on 33 patients (average dose 350 MBq/mmol). The 5-, 10-, 30- and 60-min samples were analyzed to measure the fraction of activity in FLT and its glucuronide. HPLC analysis was compared against a two-step column (Sep-Pak) and metabolic rates measured using full and limited sampling. Probenecid (2 g, oral) was given to two patients to determine whether imaging of the liver improved. RESULTS: At 60 min, 74% of the blood activity was unmetabolized (range 57-85%). HPLC and Sep-Pak gave comparable results (r=0.97; average difference 2.1%). For kinetic analysis, eight venous samples were sufficient to accurately measure total activity; for metabolite analysis, a single sample at 60 min yielded data with mean errors of 2.2%. The metabolic rate correlated with average SUV (r2=0.85; p=0.0002). An aorta input function gave kinetic results comparable to venous blood (r2=0.82). Probenecid did not improve imaging of the liver. CONCLUSION: Dynamic measurements of FLT retention can be used to calculate metabolic rates using a limited set of samples and correction for metabolites measured in a single sample obtained at 60 min.

Computer Simulation↗

[Intravitreal injection of cidofovir in cytomegalovirus retinitis].

BACKGROUND: CMV retinitis is the most common opportunistic ocular infection and the main cause of blindness in AIDS patients with a T-helper cell count < or = 50/microliter. Cidofovir is a nucleotide analogue with a long half-life time after phosphorylation intracellularly. It is effective against CMV and can be given intravenously and intravitreally. The aim was to offer an alternative therapy for CMV retinitis to patients who could not receive standard treatment because of contraindications or refused it. The efficacy and tolerance of intravitreal injections of cidofovir should be evaluated. PATIENTS AND METHODS: We treated 16 eyes of 12 patients. The total number of injections with 15 micrograms of cidofovir each was 49, with an average of 3 injections per eye. The duration of follow-up was 75-295 days (median 170 days). Probenecid was given concomitantly. Injections were repeated after 6-10 weeks. Secondary prophylaxis of CMV organ infection was done with oral ganciclovir. RESULTS: Within a few days all areas with active retinitis turned into scars following the first injection. Under consequent treatment no reactivation was observed. Four eyes developed a mild iritis with hypotony within a mean time of 12 days after injection. All responded rapidly to topical steroids. None had a persisting loss of vision. Two eyes developed cystoid macular edema (CME). Two patients stopped anti-CMV treatment (ganciclovir orally and injections), followed by a recurrence after an average of 64-days. CONCLUSIONS: Intravitreal injection therapy with 15 micrograms cidofovir and concomitant oral probenecid is a valuable and safe alternative treatment for CMV retinitis in AIDS patients. Its main complication is iritis with hypotony, which is effectively treatable with topical steroids. No complications caused by the injection technique itself were noted. The occasional observation of CME in otherwise quiet eyes, however, is probably drug-related.

AIDS-Related Opportunistic Infections↗

Voltage-driven p-aminohippurate, chloride, and urate transport in porcine renal brush-border membrane vesicles.

p-Aminohippurate (PAH) and urate are secreted into the proximal tubule lumen across the brush-border membrane. Here we used brush-border membrane vesicles from pig kidney to study PAH and urate transport. Efflux and influx of [3H]PAH were influenced by K+-diffusion potentials indicating electrogenic PAH transport. An outside>inside PAH concentration difference accelerated voltage-sensitive, Na+-coupled D-glucose uptake as efficiently as did an outside>inside Cl- concentration difference, suggesting comparable conductances for PAH and Cl- in brush-border membrane vesicles. Up to 1 mM of the uricosurics indacrinone, tienilic acid, losartan and probenecid, as well as of the stilbenes, DIDS and SITS, and of the loop diuretics furosemide and bumetanide inhibited voltage-driven PAH uptake, but not, or only slightly, voltage-driven Cl- uptake. Voltage-driven [14C]urate uptake, however, was inhibited by 0.1 mM DIDS, 0.2 mM losartan and 0.5 mM probenecid to a similar extent as [3H]PAH uptake. One millimolar pyrazinoic acid, oxonate, xanthine and adenosine inhibited neither [3H]PAH nor [14C]urate uptake. These results suggest that PAH and urate share an anion conductance which is distinct from the Cl- conductance and is probably not the same as a recently identified urate channel (Leal-Pinto E et a]. J Biol Chem 272:617-625, 1997).

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

Interactions of stevioside and steviol with renal organic anion transporters in S2 cells and mouse renal cortical slices.

PURPOSE: Our previous studies have shown that both stevioside and steviol inhibited transepithelial transport of para-aminohippurate (PAH) in isolated rabbit renal proximal tubules by interfering with organic anion transport system. The current study examined the direct interactions of stevioside and steviol with specific organic anion transporters. METHODS: S2 cells expressing human organic anion transporters (hOAT1, hOAT2, hOAT3, and hOAT4) and an intact renal epithelium were used to determine the inhibitory effect of stevioside and steviol on organic anion transport. RESULTS: Stevioside at 0.5-1 mM showed no interaction with any OAT. In contrast, steviol markedly inhibited substrate uptake in all S2hOAT cells. Steviol had low IC50 for hOAT1 (11.4 microM) and hOAT3 (36.5 microM) similar to that of probenecid, whereas IC50 for hOAT2 (1000 microM) and hOAT4 (285 microM) was much higher. Results obtained in mouse renal cortical slices were very similar; that is, stevioside was without inhibitory effect and steviol was a potent inhibitor of PAH and estrone sulfate (ES) transport. CONCLUSIONS: Stevioside has no interaction with human or mouse OATs. In contrast, steviol interacts directly with human OATs, in particular, hOAT1 and hOAT3, with a potency approximating probenecid, suggesting that the inhibition of OAT-mediated transport by steviol could alter renal drug clearance.

Animals↗

p-Aminohippurate transport in basal-lateral membrane vesicles from rabbit renal cortex: stimulation by pH and sodium gradients.

p-Aminohippuric acid (PAH) uptake was studied in basal-lateral membrane vesicles prepared from rabbit renal cortex. An outwardly directed hydroxyl gradient (pHo = 6.0, pHi = 7.6) stimulated PAH uptake slightly over that when the internal and external pH values were equal at 7.6. A 100 mM sodium gluconate gradient directed into the basal-lateral membrane vesicles increased PAH uptake about 2-fold over that when N-methyl-D-glucamine or potassium gluconate gradients were present. When hydroxyl and sodium gradients were simultaneously imposed (pHo = 6.0, pHi = 7.6 and 100 mM sodium gluconate extravesicularly) PAH uptake was stimulated greater than with the pH or Na+ gradient alone. In fact, an 'overshoot' was observed. Countertransport experiments showed that either intravesicular PAH or intravesicular PAH and Na+ could stimulate 3H-PAH uptake. Probenecid, an inhibitor of organic anion transport, inhibited both the hydroxyl-stimulated and Na+ gradient-stimulated PAH uptake but the greatest inhibition by probenecid was seen when the hydroxyl and sodium gradients were both present. Thus, it is proposed that the driving force for PAH accumulation across the basal-lateral membrane of the proximal tubule is a transport system which moves Na+ and PAH into the cell for an hydroxyl ion leaving the cell, i.e. a sodium-dependent anion-anion exchange system.

Aminohippuric Acids↗

Riboflavin uptake by native Xenopus laevis oocytes.

The existence of a membrane-associated uptake carrier for riboflavin (RF) is demonstrated in Xenopus oocytes. Uptake of low (0.017 microM) and high (3 microM) concentrations of RF was linear with time for up to 2 hours, and occurred with little initial binding to oocytes, and little metabolism. Uptake of RF was found to be independent of extracellular pH and Na+. The initial rate of RF uptake was saturable as a function of concentration with an apparent Km of 0.41 +/- 0.02 microM and a Vmax of 2.86 +/- 0.04 fmol/oocyte per h. Uptake of 3H-RF was inhibited by unlabeled RF and by the structural analogs lumiflavin, isoriboflavin (iso-RF), 8-aminoriboflavin (8-NH2-RF), 8-hydroxyriboflavin (8-OH-RF), and lumichrome, but was not affected by flavin adenine dinucleotide (FAD), D-ribose or lumazine. Uptake of RF was significantly retarded by the metabolic inhibitor 2,4-dinitrophenol. The sulfhydryl group-modifying reagents p-chloromercuriphenylsulfonate (pCMPS), p-chloromercuribenzoate (pCMB), N-ethylmaleimide and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole (NBD-Cl) all caused significant inhibition in RF uptake. The inhibitory effect of pCMPS was completely reversed by treatment of pCMPS-pretreated cells with reducing agents. While the transmembrane transport inhibitors 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS), 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and furosemide had no effect on RF uptake, amiloride and probenecid suppressed RF uptake in a dose-dependent fashion. Closer examination of the inhibition mediated by amiloride showed that it was competitive in nature with an apparent Ki of approximately 1.8 mM, whereas the inhibition induced by probenecid was nonspecific. Together, these findings indicate that Xenopus oocytes possess an endogenous, specific, membrane-associated carrier-mediated uptake system for RF. The results also demonstrate the usefulness of Xenopus oocytes as a model system with which to study the RF transport event across biological membranes, which should further out present understanding of RF uptake by various vertebrate cells.

Amiloride↗

The renal fractional clearance of platinum antitumour compounds in relation to nephrotoxicity.

The fractional renal clearance of platinum relative to inulin was measured in the conscious rat during the period 60-70 min after injection of the nephrotoxic drug, cisplatin, or its non-nephrotoxic analogues (trans-dichlorodiammine platinum II, carboplatin or iproplatin). The fractional clearance of platinum was between 3 and 4 for cisplatin and its analogues. Platinum from cisplatin and its trans isomer is essentially irreversibly bound whilst that from carboplatin and iproplatin is largely reversibly bound to blood proteins. Probenecid and triethanolamine both caused an increase whereas furosemide caused a decrease in the fractional clearance of total platinum from cisplatin. Choline chloride had no nett effect on the fractional clearance of total platinum. Both furosemide and triethanolamine made no significant difference to the severity of cisplatin induced nephrotoxicity. However, probenecid enhanced cisplatin induced nephrotoxicity and choline chloride was capable of blocking cisplatin induced nephrotoxicity. We conclude that the renal tubular transport of platinum is not per se responsible for the nephrotoxicity of platinum compounds. However, in the case of cisplatin, or one of its metabolites, renal tubular transport may be a prerequisite for nephrotoxicity.

Animals↗

Effects of morphine on the turnover of brain catecholamines and serotonin in rats-chronic morphine administration.

The turnover of brain monoamine was studied in rats in which different degrees of tolerance to and dependence on morphine were induced by pellet implantation. The degree of tolerance to morphine was assessed by measuring the increase in effective dose for an antinociceptive effect (vocalization test). The rate of depletion of brain dopamine (DA) and serotonin (5-ht) after alpha-methyl-p-tyrosine (AMT) or alpha-propyl-dopacetamide (dopacetamide) was not changed by chronic morphine treatment. In contrast, the accumulation of brain homovanillic acid HVA) and 5-hydroxyindoleacetic acid (5-HIAA) after probenecid was significantly increased, but there was no correlation between the biochemical changes and the degree of tolerance/dependence of the animals; at a very high degree of dependence 5-HIAA accumulation even became normal. In rats in which smaller amounts of morphine were repeatedly injected every 8 hr for 1 week the increased accumulation of HVA and 5-HIAA persisted in spite of complete tolerance to the antinociceptive effect. The rate of depletion of brain noradrenaline (NA) after AMT or dopacetamide was not changed and the accumulation of brain 3-methoxy-4-hydroxy-phenylglycol sulphate (MHPG-SO4) after probenecid was not affected in most chronic morphine groups. In the group with the highest degree of tolerance/dependence NA depletion after AMT was even retarded. The results suggest that chronic morphine treatment increases the synthesis and the intraneuronal destruction of newly synthesized DA and 5-HT without changing the rate of functional utilization of the monoamines. It is unlikely that the changes in monoamine metabolism are causally related to processes leading to morphine tolerance/dependence.

3-Methoxy-4-hydroxyphenylethanol↗

Regional rat brain levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid: concurrent fluorometric measurement and influence of drugs.

A concurrent semi-automatic fluorometric assay technique for 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), is described. The method is based on a rapid manually performed isolation of DOPAC and HVA on small columns of Sephadex G-10 followed by an automated fluorometric detection with a continuous flow system. DOPAC and HVA were measured in the corpus striatum, nucleus accumbens and olfactory tubercle of the rat, under normal conditions and after treatment with amphetamine, apomorphine, clozapine, haloperidol, morphine, oxotremorine, pargyline, probenecid, sulpiride and thioridazine. Clozapine, morphine, sulpiride and oxotremorine induced the most pronounced rise of DA metabolites in the nucleus accumbens. Probenecid produced a DOPAC accumulation in the nucleus accumbens. Striking differences were observed between the DOPAC/HVA ratios in the different structures of control animals. The concurrent assay enables a rapid screening of the action of drugs in regional DA metabolism.

3,4-Dihydroxyphenylacetic Acid↗

Effects of single and multiple doses of desipramine (DMI) on endogenous levels of 3-methoxy-4-hydroxyphenylglycol-sulfate (MOPEG-SO4) in rat brain.

A single administration of desipramine (DMI) (10 mg/kg, i. p.) decreased brain levels and probenecid-induced accumulation rate of 3-methoxy-4-hydroxyphenylglycol-sulfate (MOPEG-SO4) in rats. To investigate the mechanism of this action, the interaction of DMI with NA receptor blockers and its effects on electrical stimulation were evaluated. It was found that phenoxybenzamine (20 mg/kg) or chlorpromazine (10 mg/kg) completely prevented the DMI-induced decrease in MOPEG-SO4 brain levels. On the other hand, DMI did not antagonize the increase in MOPEG-SO4 induced in the cortex-hippocampus by stimulation of the locus coeruleus. These observations indicate that the effect of DMI on MOPEG-SO4 is more likely to be due to a reduction of neuronal impulse flow mediated by a negative feed-back mechanism resulting from impairment of reuptake than to a direct effect on NA catabolism. In contrast to the effect of a single dose, the repeated administration of DMI (10 mg/kg, twice a day for 3 days) did not significantly reduce the rate of probenecid-induced accumulation of MOPEG-SO4. This development of tolerance to the metabolite-decreasing effects of DMI indicates that complex adaptive changes occur in the NA system upon repeated DMI administration.

Animals↗

Mediation of cellular anion detoxification in leukemic cells by unidirectional efflux pumps.

Methotrexate influx in L1210 cells is mediated almost entirely by a single system, whereas efflux occurs via three routes, the influx carrier functioning in reverse and two additional systems which are operationally unidirectional. The two unidirectional routes show considerable similarities in energy-dependence and inhibitor sensitivities but can be separated by their differential inhibition by bromosulfophthalein (BSP), probenecid, and vincristine. The predominant route is inhibited by BSP and vincristine, whereas the other route is sensitive to probenecid. A search for additional anion substrates for the unidirectional efflux systems for methotrexate led to the finding that cholate exits L1210 cells via the same two unidirectional efflux systems as methotrexate. Cholate efflux is carrier-mediated, energy-dependent, and unidirectional, and it can be inhibited by several compounds which inhibit the efflux of methotrexate. Moreover, the same concentration of each compound which produced a half-maximal inhibition of methotrexate efflux also inhibited the efflux of cholate by 50%. Cholate efflux occurred predominantly (85%) via the BSP-sensitive route. The observation that methotrexate and cholate share the same efflux systems in L1210 cells suggest that perhaps other large anions are also accommodated by these systems since methotrexate and cholate differ in net negative charge and have few common structural features. The hypothesis advanced from these studies has been that the function of the unidirectional efflux systems is to extrude various organic anion catabolites which might otherwise become toxic if allowed to accumulate within cells. Possible intracellular anions in this latter category include sulfonated or carboxylated steroids, bilirubin, and products of vitamin D and prostaglandin catabolism. Unidirectional efflux pumps have been identified for other anionic compounds including cyclic AMP and oxidized glutathione, and in both cases similarities were apparent with the efflux of methotrexate and cholate. The most compelling comparison was with prostaglandin A1 which inhibited the efflux of cyclic AMP, methotrexate, and cholate half-maximally at the same low concentration of 0.1 microM. Energy-dependent unidirectional efflux pumps for large neutral or cationic drugs have also been identified in cells with acquired multidrug resistance. The latter efflux activity is thought to be mediated by a membrane glycoprotein (p170) which is also sensitive to several of the various inhibitors (reserpine, verapamil, and quinidine) which reduce the efflux of methotrexate and cholate.

Animals↗

p-aminohippurate uptake by syncytial microvillous membrane vesicles of human term placenta.

The mechanism of uptake of p-aminohippurate (PAH) by syncytial microvillous membrane vesicles of human term placenta was investigated. Initial PAH uptake and efflux were increased in the presence of a pH-gradient and a Cl(-)-gradient, respectively. Forced negative and positive membrane potentials did not influence the uptake, which indicated that the transport is not electrogenic. The pH-dependent increase is probably the result of a higher rate of diffusion due to a lower degree of dissociation of PAH. Because several organic anions failed to transstimulate PAH uptake and FCCP did not decrease the uptake in the presence of an inwardly directed H(+)-gradient, ruling out a PAH/OH- antiport, an anion exchange system does not appear to be present in these membranes. Since electrogenicity and anion exchange seem not to be involved in the Cl(-)-dependent increase, an allosteric effect of Cl- on the transporter might be possible. Various organic anions were able to inhibit pH-stimulated PAH uptake significantly. Kinetic analysis of the probenecid sensitive part of uptake provided further evidence for mediated transport of PAH (Km = 7.4 +/- 2.6 mM and Vmax = 2.0 +/- 0.4 nmol/mg/15 s). Non-inhibitable diffusion accounted for the main part of total transport. Concentration dependent inhibition of PAH transport by probenecid showed a Ki of 2.5 +/- 0.9 mM. It is concluded that human placental syncytial microvillous membrane vesicles possess a low affinity transport mechanism for PAH with low specificity. The importance of this system, for placental excretion of anionic drugs, will depend on the intrasyncytial concentration of these drugs, caused by the transport across the basal membrane.

Biological Transport↗

Effects of reserpine and L-cysteine and glutathione depletion on 2-bromoethylamine hydrobromide-induced tubular necrosis in Swiss ICR mice.

Female Swiss ICR mice were injected ip with 100 or 300 mg 2-bromoethylamine hydrobromide (BEA)/kg body weight. Male Swiss ICR mice were subjected to water deprivation, or treated with 5% dextrose in water, dimethylsulphoxide, piperonyl butoxide, SKF-525A, sodium phenobarbital, beta-naphthoflavone, probenecid, reserpine, diethyl maleate, buthionine sulphoximine or L-cysteine. Urine collected sequentially from male Swiss ICR mice given 300 mg BEA/kg body weight was analysed for glucose, protein, pH and specific gravity. Female mice were less sensitive to BEA than were male mice. Diuresis, antidiuresis, treatment with cytochrome P-450 inducers and inhibitors, and the antioxidant dimethyl-sulphoxide had no effect on the incidence or severity of tubular necrosis (TN) induced by BEA. Probenecid and L-cysteine decreased the severity, but they had no effect on the incidence of TN. Glutathione depletion by diethyl maleate and inhibition of glutathione synthesis by buthionine sulphoximine decreased the dose of BEA necessary to cause TN; buthionine sulphoximine was more effective than diethyl maleate. Reserpine decreased both the incidence and severity of TN. Glycosuria, aciduria and decreased urinary specific gravity occurred before morphological changes were seen under the microscope, indicating that the functional changes precede the morphological changes. These data indicate that glutathione is important in protecting against BEA-induced TN, that BEA or a metabolite is concentrated in the tubule epithelium by way of anion transport, and that vasoconstriction contributes to the development of BEA-induced TN.

Animals↗

Potentiation of methotrexate-induced gastrointestinal toxicity by non-steroidal anti-inflammatory drugs (NSAIDs) and vincristine.

Inhibition of intestinal nutrient absorption by the folate antagonist methotrexate (MTX) and the effects of several organic acid drugs and vincristine on MTX-induced gastrointestinal toxicity were investigated. Male Swiss-Webster mice received MTX, 25 mg/kg, i.p. once daily for 4 successive days. Using the everted sac technique, the rates of D-glucose and L-tyrosine transport were decreased by MTX to 10.9 and 6.3 mumol/g/h from control values of 35.0 and 10.0 mumol/g/h, respectively. Probenecid, sodium salicylate, phenylbutazone, or vincristine administered simultaneously with MTX, further decreased the rates of D-glucose transport to 3.6, 2.0, 0.8, and 2.6 mumol/g/h, respectively, and the rates of L-tyrosine transport to 1.2, 1.9, 0.6 and 0.9 mumol/g/h, respectively. When intestinal sacs from untreated animals were exposed to MTX (10(-3) M) on the serosal side only, the drug had no significant effect on the rate of transport of D-glucose or L-tyrosine. The rate of lactate production in everted intestinal sacs from MTX treated animals decreased to 11.8 from a control value of 30.3 mumol/g/h. Co-administration of phenylbutazone with MTX further decreased the rate of lactate production to 8.2 mumol/g/h. Body weight loss caused by MTX treatment (15.0%) was potentiated by the concurrent administration of probenecid (19.4%), salicylate (22.4%), phenylbutazone (23.0%) or vincristine (22.8%). These results demonstrate that vincristine and several commonly used organic acid drugs can potentiate the inhibitory effect of MTX on intestinal nutrient absorption. Thus, MTX dosage adjustment may be required in patients receiving such drugs.

Animals↗

Metabolism of Zidovudine.

1. The anti-HIV drug zidovudine (3'-azido-2',3'-dideoxythymidine; ZDV) has three important pathways of metabolism. ZDV is a prodrug and must be phosphorylated in lymphocytes in order to exert its antiviral action. However, in quantitative terms this is a minor pathway probably accounting for less than 1% of the overall metabolic profile. The predominant pathway of metabolism is glucuronidation to GZDV and the metabolite is renally excreted. A further metabolite, derived by reduction of the azido moiety is 3'-amino-3'-deoxythymidine (AMT). 2. Zidovudine glucuronidation has been characterised in human liver microsomes. A number of drugs (e.g., naproxen, indomethacin and probenecid) have been shown to inhibit the in vitro conjugation of ZDV. Some of these drugs have also been co-administered with ZDV in HIV-positive patients. Significant pharmacokinetic interactions have been demonstrated with probenecid, naproxen and fluconazole. 3. 3'-amino-3'-deoxythymidine formation is probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Peak plasma concentrations of AMT are approximately 10-15% of ZDV in patients. This is a potentially important metabolite because of its alleged cytotoxicity. 4. Measurement of intracellular ZDV phosphates in patients provides the key to our understanding of both the efficacy and toxicity of ZDV. Important recent work has demonstrated that as patients deteriorate (i.e., CD4 counts decrease below 100 x 10(6)/L), there is a corresponding increase in intracellular ZDV-monophosphate. This could have toxicological implications.

AIDS-Related Complex↗