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PubMed1995

Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients.

The pharmacokinetics of cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 h (n = 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean +/- standard deviation total clearance of the drug from serum (148 +/- 25 ml/h/kg; n = 25) approximated renal clearance (129 +/- 42 ml/h/kg; n = 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 +/- 21 ml/h/kg; n = 12). These data indicate that active tubular secretion played a significant role in the clearance of cidofovir. The steady-state volume of distribution of cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of cidofovir at a 3.0-mg/kg dose. At higher cidofovir doses, probenecid appeared to block tubular secretion of cidofovir and reduce its renal clearance to a level approaching glomerular filtration.

AIDS-Related Opportunistic Infections↗
PubMed1998

Pharmacokinetics of sparfloxacin in the serum and vitreous humor of rabbits: physicochemical properties that regulate penetration of quinolone antimicrobials.

We have used a recently described animal model to characterize the ocular pharmacokinetics of sparfloxacin in vitreous humor of uninfected albino rabbits following systemic administration and direct intraocular injection. The relationships of lipophilicity, protein binding, and molecular weight to the penetration and elimination of sparfloxacin were compared to those of ciprofloxacin, fleroxacin, and ofloxacin. To determine whether elimination was active, elimination rates following direct injection with and without probenecid or heat-killed bacteria were compared. Sparfloxacin concentrations were measured in the serum and vitreous humor by a biological assay. Protein binding and lipophilicity were determined, respectively, by ultrafiltration and oil-water partitioning. Pharmacokinetic parameters were characterized with RSTRIP, an iterative, nonlinear, weighted, least-squares-regression program. The relationship between each independent variable and mean quinolone concentration or elimination rate in the vitreous humor was determined by multiple linear regression. The mean concentration of sparfloxacin in the vitreous humor was 59.4% +/- 12.2% of that in serum. Penetration of sparfloxacin, ciprofloxacin, fleroxacin, and ofloxacin into, and elimination from, the vitreous humor correlated with lipophilicity (r2 > 0.999). The linear-regression equation describing this relationship was not improved by including the inverse of the square root of the molecular weight and/or the degree of protein binding. Elimination rates for each quinolone were decreased by the intraocular administration of probenecid. Heat-killed Staphylococcus epidermidis decreased the rate of elimination of fleroxacin. Penetration of sparfloxacin into the noninflamed vitreous humor was greater than that of any quinolone previously examined. There was an excellent correlation between lipophilicity and vitreous entry or elimination for sparfloxacin as well as ciprofloxacin, fleroxacin, and ofloxacin. There are two modes of quinolone translocation into and out of the vitreous humor: diffusion into the eye and both diffusion and carrier-mediated elimination out of the vitreous humor.

Animals↗
PubMed2003

Effects of organic anion, organic cation, and dipeptide transport inhibitors on cefdinir in the isolated perfused rat kidney.

Cefdinir (Omnicef; Abbott Laboratories) is a cephalosporin antibiotic primarily eliminated by the kidney. Nonlinear renal elimination of cefdinir has been previously reported. Cefdinir renal transport mechanisms were studied in the erythrocyte-free isolated perfused rat kidney. Studies were performed with drug-free perfusate and perfusate containing cefdinir alone to establish the baseline physiology and investigate cefdinir renal elimination characteristics. To investigate cefdinir renal transport mechanisms, inhibition studies were conducted by coperfusing cefdinir with inhibitors of the renal organic anion (probenecid), organic cation (tetraethylammonium), or dipeptide (glycylsarcosine) transport system. Cefdinir concentrations in biological samples were determined using reversed-phase high-performance liquid chromatography. Differences between treatments and controls were evaluated using analysis of variance and Dunnett's test. The excretion ratio (ER; the renal clearance corrected for the fraction unbound and glomerular filtration rate) for cefdinir was 5.94, a value indicating net renal tubular secretion. Anionic, cationic, and dipeptide transport inhibitors all significantly affected the cefdinir ER. With probenecid, the ER was reduced to 0.59, clearly demonstrating a significant reabsorptive component to cefdinir renal disposition. This finding was confirmed by glycylsarcosine studies, in which the ER was elevated to 7.95, indicating that reabsorption was mediated, at least in part, by the dipeptide transporter system. The effects of the organic cation tetraethylammonium, in which the ER was elevated to 7.53, were likely secondary in nature. The anionic secretory pathway was found to be the predominant mechanism for cefdinir renal excretion.

Animals↗
PubMed1974

Human pharmacokinetics of BL-P1654 compared with ampicillin.

BL-P1654 is a new ureido-penicillin which has significant activity against both pseudomonas and klebsiella. Its pharmacokinetics were evaluated in five studies in four healthy adult male volunteers after 1-g doses given as: 5- and 30-min intravenous infusions, a 30-min infusion 1 h after the oral administration of 1 g of probenecid, and an intramuscular injection. For comparison, volunteers also received a 30-min infusion of 1 g of ampicillin. Serum levels of the antibiotic were found to fit a two-compartment open model using a Burroughs-5500 computer. After a 30-min infusion, peak serum levels of BL-P1654 (72.8 mug/ml [standard deviation] +/- 5.9) were 50% greater than those of ampicillin (53.6 +/- 8.9). Six hours later, the relative difference was even greater (4.58 +/- 0.25 versus 0.35 +/- 0.09). At 75 min after the 1-g intramuscular injection of BL-P1654, peak serum levels averaged 28.4 +/- 10.3 mug/ml. The half-life of BL-P1654 (2.04 h) was significantly longer than for ampicillin (1.15 h), and the renal clearances of BL-P1654 and ampicillin were 79 versus 244 ml/min per 1.73 m(2), respectively. Probenecid produced no significant change in blood levels, volume of distribution, half-life, or renal clearance, indicating that there is no net tubular secretion of this antibiotic.

Ampicillin↗
PubMed1978

Clinical experience in the use of cefuroxime in gonorrhoea.

Cefuroxime, a new antibiotic derived from cephalosporin-C which is very stable in the presence of beta-lactamases produced by Gram-negative organisms, was used to treat 856 male patients and 340 female patients with uncomplicated gonorrhoea. In men the drug was used in three different doses, 1.5 g, 1 g, and 750 mg plus 1 g probenecid; in women 1 g and 750 mg cefuroxime plus 1 g probenecid was used. Cure rates ranged from 94.8% to 99.3%. The antibiotic was well tolerated and was free from side effects. Cefuroxime would be a valuable and efficient substitute for penicillin in the treatment of gonorrhoea due to beta-lactamase-producing strains of gonococci.

Cephalosporins↗
PubMed1979

Comparison of minocycline and ampicillin in gonococcal urethritis.

A prospective, randomised, single-blind trial was carried out to compare the efficacy and tolerability of minocycline and ampicillin in the treatment of gonorrhoea in men. One hundred and twenty men were treated with minocycline 300 mg and 121 men with ampicillin 2 g and probenecid 1 g. Cure rates were similar in both groups of patients. There were few side effects. Of 135 strains of Neisseria gonorrhoeae tested to different concentrations of minocycline and penicillin, two were resistant to penicillin (minimum inhibitory concentration (MIC) greater than or equal to 0.1 microgram/ml) and seven to minocycline (MIC greater than 1.0 microgram/ml). The incidence of PGU was 31% in those patients treated with minocycline and 34% in those treated with ampicillin plus probenecid, the difference not being statistically significant. PGU occurred more often after treatment with minocycline than in previous studies.

Adult↗
PubMed1986

Single dose cefoxitin in treating uncomplicated gonorrhoea caused by penicillinase producing Neisseria gonorrhoeae (PPNG) and non-PPNG strains.

A total of 136 patients with uncomplicated gonorrhoea were treated with intramuscular cefoxitin 2 g (25 patients) or 1 g (111 patients) and oral probenecid 1 g. Cefoxitin 1 g cured 95% (42 out of 45 men and all of 14 women) with infections caused by penicillinase producing Neisseria gonorrhoeae (PPNG) strains and 98% (all of 38 men and 13 out of 14 women) with non-PPNG infections, giving an overall cure rate of 96%. The rate of postgonococcal urethritis (PGU) in men treated with 1 g cefoxitin was 28%. No serious side effects of treatment were observed in patients treated with either dose. The failure rate of 7% in men infected with PPNG strains who were treated with the 1 g dose is, however, disturbing. We therefore recommend that intramuscular cefoxitin 2 g and oral probenecid 1 g may be used to treat uncomplicated gonorrhoea, especially in areas where PPNG strains are common.

Cefoxitin↗
PubMed1997

Cefaclor, an alternative to third generation cephalosporins for the treatment of gonococcal urethritis in the developing world?

OBJECTIVE: To reassess the in vivo and in vitro efficacy of cefaclor for the treatment of uncomplicated gonococcal infection. DESIGN: Open clinical trail conducted in South Africa among consecutive male patients with symptoms and signs of uncomplicated urethritis and laboratory evidence of gonorrhoea. METHODS: Patients were treated with 3 g of cefaclor plus 1 g probenecid as a single dose. Urethral specimens were cultured for Neisseria gonorrhoeae at the initial visit and at follow up. Patients were considered cured if follow up cultures were negative. Treatment was considered to have failed in the patients infected with identical gonococcal strains at the initial and at the control visit. Those with evidence of infection at the follow up visit were administered 400 mg of ofloxacin and doxycycline 100 mg twice daily for 7 days. Minimal inhibitory concentrations (MICs) of cefaclor were determined by an agar dilution technique on the gonococcal isolates from the study subjects. The results were compared with those of isolates from three other African countries. RESULTS: Of 155 patients evaluated, 151 were cured (97%). Thirty per cent of the patients complained of adverse effects, mainly gastrointestinal. Even though MICs for the isolates from the three other African countries were significantly higher than those for the isolates from the study, none was considered resistant to cefaclor in vitro. MICs were markedly influenced by the type of test medium used. CONCLUSION: The trial demonstrated the efficacy of a single oral dose of cefaclor with probenecid for the treatment of uncomplicated gonococcal urethritis in South Africa. Its potential as an alternative therapy to third generation cephalosporins deserves to be further investigated.

Administration, Oral↗
PubMed1981

Cardiac atrial factor--an endogenous diuretic?

An extract of rat heart atria causes a saluresis in bioassay rats. When organic acid secretion in the proximal tubule was blocked by probenecid, the saluretic response to the extract was significantly reduced. Similarly, the natriuretic response to acute hypervolemia was reduced by probenecid administration. The data indicate that the atrial natriuretic factor, like the "loop" diuretic drugs, requires proximal tubular secretion for maximal renal activity. Furthermore, the factor may play a role in the renal response to acute blood volume expansion.

Animals↗
PubMed1997

Measurement of mitochondrial calcium in single living cardiomyocytes by selective removal of cytosolic indo 1.

The aim of the present study was to determine whether, in indo 1 acetoxymethyl ester (AM)-loaded rat cardiomyocytes, it was possible to remove cytosolic but not mitochondrial indo 1 by promoting loss of cytosolic indo 1 through plasma membrane anion pumps (which are blocked by probenecid). Isolated rat ventricular myocytes were loaded with indo 1-AM under conditions (15 min at 30 degrees C) in which about half of the dye is located within mitochondria. Cells were then maintained at 25 degrees C for 2.5 h followed by incubation at 37 degrees C for 1.5 h. After this "heat treatment," the myocyte fluorescence signal was 44% of the value of cells measured before heat treatment, and loss of fluorescence was prevented by 1 mM probenecid. The remaining fluorescence was shown to originate from mitochondria, since 1) Ca2+ uptake and efflux could be inhibited by ruthenium red and clonazepam, respectively, and 2) low concentrations of digitonin, which release only cytosolic marker enzymes, decreased fluorescence of untreated myocytes but had little effect on the fluorescence signal of heat-treated cells. We conclude that heat treatment selectively removes cytosolic indo 1, leaving a signal due to mitochondrial indo 1 only.

Animals↗
PubMed2001

Nifedipine modulation of biliary GSH and GSSG/ conjugate efflux in normal and regenerating rat liver.

Canalicular glutathione secretion provides the major driving force for bile acid-independent bile flow (BAIF), although the pathways involved are not established. The hypothesis that GSH efflux proceeds by a route functionally distinct from the high-affinity, low-capacity, mrp2-mediated pathway was tested by using perfused rat liver and three choleretic compounds that modify biliary secretion of GSH (the dihydropyridine nifedipine and organic anion probenecid) or GSSG [sodium nitroprusside (SNP)]. Whereas nifedipine (30 microM) stimulated GSH secretion and blocked SNP-stimulated GSSG efflux and choleresis, SNP (1 mM) was ineffective against nifedipine-stimulated GSH efflux or BAIF, suggesting that most GSSG exits through a GSH-inhibitable path independent of high-affinity GSSG/glutathione conjugate transport. Three observations support this proposal. SNP, but not nifedipine, significantly inhibited bromosulfophthalein (BSP, 1 microM) excretion. Probenecid (1 mM) blocked resting or nifedipine-stimulated GSH secretion but only weakly inhibited BSP excretion. Glutathione, but not BSP, efflux capacity was reduced following partial hepatectomy. We suggest GSH efflux is mediated by a high-capacity organic anion pathway capable of GSSG transport when its high-affinity route is saturated.

Animals↗
PubMed1992

Maturational differences in acetazolamide-altered pH and HCO3 of choroid plexus, cerebrospinal fluid, and brain.

The carbonic anhydrase inhibitor acetazolamide is useful for analyzing ion transport, pH regulation, and fluid formation in developing central nervous system. We used the 14C-labeled dimethadione technique to measure alterations in steady-state pH, and to estimate the HCO3 concentration [HCO3], in choroid plexus (CP), cerebrospinal fluid (CSF), and cerebral cortex of 1- and 3-wk-old Sprague-Dawley rats treated with acetazolamide or probenecid. These drugs can suppress transport of HCO3 and other anions in some cells, consequently altering intracellular pH. In 1-wk-old infant rats whose CSF secretory process is incompletely developed, 1 h of acetazolamide treatment did not significantly change CP intracellular pH or [HCO3]. However, in 3-wk-old rats, in which the ability of CP to secrete ions and fluids is almost fully developed, acetazolamide caused marked increases in CP cell intracellular pH and [HCO3]. In contrast, acetazolamide-induced alkalinization was not observed in CSF or cerebral cortex of the 1- and 3-wk-old animals. The other test agent, probenecid (an inhibitor of anion transport but not of carbonic anhydrase), did not alter the pH of any region at any age investigated. Overall, the results are interpreted in light of developmental changes in carbonic anhydrase and previous findings from kinetic analyses of ion-translocating systems in CP. Acetazolamide may interfere with a CP apical membrane HCO3 extrusion mechanism not fully operational in infant rats.

Acetazolamide↗
PubMed2006

Transport of estrone sulfate by the novel organic anion transporter Oat6 (Slc22a20).

Recently, a novel Slc22 gene family member expressed in murine olfactory mucosa was identified and based on sequence homology proposed to be an organic anion transporter [Oat6 (Slc22a20); J. C. Monte, M. A. Nagle, S. A. Eraly, and S. K. Nigam. Biochem Biophys Res Commun 323: 429-436, 2004]. However, no functional data for Oat6 was reported. In the present study, we demonstrate that murine Oat6 mediates the inhibitable transport of estrone sulfate using both Xenopus oocyte expression assay and Chinese hamster ovary (CHO) cells stably transfected with mOat6 (CHO-mOat6). Uptake was virtually eliminated by probenecid and the anionic herbicide 2,4-dichlorophenoxyacetate. The organic anions ochratoxin A, salicylate, penicillin G, p-aminohippurate, and urate inhibited mOat6-mediated accumulation to varying degrees. Transport of estrone sulfate by mOat6 was demonstrated to be saturable, and K(m) estimates of 109.8 +/- 22.6 microM in oocytes and 44.8 +/- 7.3 microM in CHO-mOat6 cells were obtained. Inhibitory constants for 2,4-dichlorophenoxyacetate (15.7 +/- 2.0 microM), salicylate (49.0 +/- 4.4 microM), probenecid (8.3 +/- 2.5 microM), and penicillin G (1,450 +/- 480 microM) were also determined. Accumulation of estrone sulfate mediated by mOat6 was significantly trans-stimulated by glutarate, indicating that mOat6 functions as an organic anion/dicarboxylate exchanger. These data demonstrate for the first time that the novel murine gene Oat6 (Slc22a20) encodes a functional organic anion transporter and mOat6 is indeed the newest member of the OAT gene family.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1980

Renal handling of phenol red. IV. Tubular localization in rabbit and rat kidney in vivo.

In the rabbit kidney accumulation of phenol red in cortex tissue is directly related to phenol red excretion. In histological preparations of rabbit cortex the major part of phenol red is localized to the pars recta of proximal tubules at low plasma concentrations of dye. The extra uptake of dye by the pars recta is abolished by administration of a high dose of probenecid and also by high plasma dye concentrations, when dye secretion is low relative to tubular reabsorption. Tissue accumulation of phenol red in the rat exhibits features similar to those in the rabbit. However, extra dye uptake in the pars recta is maintained after administration of probenecid, and disappears after intravenous injection of phenol red during ureteral occlusion to impede access of dye from tubule fluid to the luminal membrane. It is concluded that in the rabbit phenol red uptake by the pars recta probably is due to tubular secretion across the peritubular membrane, whereas in the rat extra uptake of dye by this segment is consistent with uptake at the luminal cell membrane.

Animals↗
PubMed1980

Accumulation of [14C]urate and [3H]PAH in isolated proximal tubular segments of the rabbit kidney.

Segments of rabbit proximal tubules (S1, S2, and S3) were incubated (30 min, 37 degrees C, pH 7.4) in Ringer solution (under O2) containing [14C]urate or [3H]PAH and probenecid, pyrazinoic acid (PZA), urate, or PAH, all at 1 mM. The ratio [14C]urate (counts/min per nanoliter of tubular cell water)/(counts/min per nanoliter of incubation medium) (T/M) reached 2.92 +/- 0.31 (mean +/- SE; n = 15), 6.08 +/- 0.42 (n = 42), and 1.72 +/- 0.31 (n = 14) for S1, S2, and S3 segments, respectively. In these segments the uptake of [3H]PAH was 22.7 +/- 4.6 (n = 19), 133 +/- 18.9 (n = 24), and 66.2 +/- 15.3 (n =0). The accumulation of [14C]urate was saturated at 2 x 10(-4) M in the medium, and that of [3H]PAH at 7 x 10(-5) M in the medium. Secretory transport was saturated at the same bath PAH concentration in perfused tubules. Urate and PAH transports inhibited each other, thus suggesting a common transport mechanism mainly located in the S2 segment. Probenecid was a strong and PZA a weak inhibitor of this transport system.

Aminohippuric Acids↗
PubMed1980

Secretion of urate in the proximal convoluted tubule of the rat.

In order to examine the transepithelial secretory flux of urate in the rat proximal tubule, simultaneous perfusions of capillaries and lumens were performed. The capillary perfusate contained [2-14C]urate in concentrations of 0.305--2.94 mM. The secretory flux of urate increased as the concentration of urate in the capillary perfusion solution was increased from 0.305 to 1.235 mM but tended toward a plateau at higher concentrations. An apparent Km of 0.41 mM and Vmax of 4.7 pmol . min-1 . mm-1 were calculated from the observed net flux and an estimated passive permeability coefficient of 0.725 pmol . min-1 . mm-1. The addition of probenecid (10(-4) M) to the capillary perfusion solution inhibited urate secretion in a manner consistent with that of a competitive inhibitor. The addition of p-chloromercuribenzoate (10(-4) M) to the capillary perfusion solution inhibited the Vmax but not the Km, suggesting a non-competitive type of inhibition. These data provide the first estimates of the apparent transport constants for urate secretion in the rat proximal tubule determined in vivo. Urate secretion is mediated by a saturable carrier-mediated system. This carrier is not affected by the presence or absence of potassium in the perfusion solution but can be inhibited by the addition of either probenecid or p-shloromercuribenzoate.

Animals↗
PubMed1981

Basis for heterogeneity of para-aminohippurate secretion in rabbit proximal tubules.

Para-aminohippurate (PAH) is secreted at different rates in S1, S2, and S3 segments of isolated perfused proximal tubules of rabbit kidney. To characterize PAH transport we determined the maximal rate of secretion (Vmax) and the apparent Michaelis constant (Km) for each segment by examining the relationship between bath concentration of PAH and net PAH secretion (Jb leads to lPAH) transposed for Lineweaver-Burk analysis. The passive component of secretion for all segments was estimated by slope analysis at relatively high concentrations of PAH, by the component of PAH secretion insensitive to inhibition by probenecid, and, additionally, in S2 segments, from PAH efflux from lumen to bath. Subtraction of the passive component from Jb leads to lPAH (probenecid method) gave Vmax values for S1, S2, and S3 segments of 1,097 +/- 336 (n = 6), 7,430 +/- 1,338 (n = 6), 1,647 +/- 138 (n = 8) X 10(-15) mol.min-1.mm-1 (+/- SE) and apparent Km values of 139 +/- 37 (n = 6), 195 +/- 37 (n = 6), and 113 +/- 16 (n = 6) X 10(-6) M, respectively. Thus, Vmax for S2 greater than S3 congruent to S1, whereas apparent Km was not consistently different among the segments. On the basis of these results we suggest that axial heterogeneity of PAH secretion may reflect an increased basolateral membrane density of PAH transporters of common affinity in the S2 segment of the proximal tubule.

Aminohippuric Acids↗
PubMed1981

Uptake of [3H]PAH and [14C]urate into isolated proximal tubular segments of the pig kidney.

Segments of proximal convoluted (PCT) and proximal straight (PST) tubules of minipigs and normal-sized pigs were microdissected (without collagenase treatment) and incubated (30 min, 37 degrees C, pH 7.4) in Ringer solution (under O2) containing [3H]PAH (3.10(-5) M) or [14C]urate (9.10(-5) M) and, in inhibitor studies, probenecid, pyrazinoic acid (PZA), urate or PAH, all at 1 mM. In both strains the uptake of [3H]PAH expressed as means T/M ratio (cpm per ml tissue water/cpm per ml incubation medium) was significantly higher (P less than 0.001) in PCT than in PST. T/M was 34.7 +/- 5.6 (SE) in 34 PCT and 2.4 +/- 0.3 in 24 PST of eight minipigs. In two normal-sized pigs the T/M was 14.1 +/- 3.6 in 15 PCT and 1.4 +/- 0.1 in six PST. Similar results were obtained for [14C]urate. In eight minipigs the T/M was 4.9 +/- 0.5 in 24 PCT and 2 +/- 0.2 in 25 PST. In normal-sized pigs the T/M was 3.8 +/- 0.3 in 35 PCT (five pigs) and 1.9 +/- 0.4 in eight PST (two pigs). In inhibitor studies urate significantly depressed the uptake of [3H]PAH, and unlabeled PAH depressed the uptake of [14C]urate. PZA significantly inhibited the uptake of [14C]urate but not that of [3H]PAH, whereas probenecid had a strong inhibitory effect on the uptake of both compounds. These results suggest that [14C]urate and [3H]PAH are transported by a transport system located mainly in the proximal convoluted tubule. These findings are in contrast to the findings obtained in rabbits in which the transport system of PAH and urate is mainly located in the proximal part of the pars recta.

Aminohippuric Acids↗