OAT1/OAT3; Pannexin-1 (Panx1) ; MRP1; transient receptor potential vanilloid 2 (TRPV2)

Probenecid 有效抑制 MRP1 和 MRP2 对 ATP 依赖性活性囊泡 N-乙基马来酰亚胺谷胱甘肽 (NEM-GS) 的吸收。随着有机阴离子浓度的增加，MRP1-ATP酶受到显着抑制。 MRP2的ATPase活性受丙磺舒(约KACT=250μM)、磺吡酮(KACT=300μM)和吲哚美辛(KACT=150μM)的影响，且ATPase激活甚至比NEM-GS更强。有机阴离子对 MRP2-ATP 酶的激活遵循钟形曲线，丙磺舒的最大值为 2 mM，磺吡酮的最大值为 800 μM，吲哚美辛的最大值为 400 μM [2]。 Probenecid 是 hTAS2R16、hTAS2R38 和 hTAS2R43 苦味受体的抑制剂。丙磺舒作用于 TAS2R 的一个子集，并通过新的变构作用机制进行抑制。丙磺舒也经常用于改善 GPCR 钙动员实验中的细胞信号传导。丙磺舒特异性抑制苦味受体 hTAS2R16 介导的细胞反应，并为使用非竞争性（变构）机制与该 GPCR 直接接触提供分子和药理学证据。

与饲喂盐水的对照小鼠相比，丙磺舒增加了 WT 小鼠的收缩力，如射血分数 (EF) 所示。在 75 mg/kg 及更高剂量的所有剂量下，在推注后 5 分钟内观察到收缩力增加（75 mg/kg、100 mg/kg 和 200 mg/kg 时的峰值变化分别为 5.26±3.35、8.40±2.80 和分别为7.32±2.52）。估计 EC50 为 49.33 mg/kg，在总共 30 分钟内以 5 分钟为间隔评估的收缩性变化显示出收缩性的剂量依赖性增加。在较长时间内接受检查的患者中，EF 保持升高至少一个小时（n=5，200 mg/kg IV）（EF 相对于基线的平均升高为 8.9±2.57）

In order to obtain a dose response curve, male C57 WT (n=39) mice 12-16 weeks of age are anesthetized with isoflurane while intravenous jugular access (IV) is obtained under a microscope. Subsequently, an echocardiographic study with both M-mode and B-mode is obtained in parasternal long axis (PSLAX) as described below. Either saline or different doses of Probenecid (increasing from 2 to 200mg/kg) are injected (bolus IV) for the initial contractility studies in WT mice.

Absorption, Distribution and Excretion
Excreted principally in the urine as monoacyl glucuronide and unchanged drug. Alkalinization of urine increases renal probenecid excretion.
PROBENECID IS COMPLETELY ABSORBED AFTER ORAL ADMIN. PEAK PLASMA CONCN ARE REACHED IN 2-4 HR. THE HALF-LIFE OF THE DRUG IN PLASMA IS DOSE DEPENDENT AND VARIES FROM LESS THAN 5 HR TO MORE THAN 8 HR.
BETWEEN 85 & 95% OF DRUG IS BOUND TO PLASMA ALBUMIN, LARGELY TO ALBUMIN. SMALL UNBOUND PORTION GAINS ACCESS TO GLOMERULAR FILTRATE; A MUCH LARGER PORTION IS ACTIVELY SECRETED BY PROXIMAL TUBULE.
IN SPITE OF ITS LOW PKA (3.4), HIGH LIPID SOLUBILITY OF UNDISSOCIATED FORM RESULTS IN VIRTUALLY COMPLETE ABSORPTION BY BACK DIFFUSION UNLESS URINE IS MARKEDLY ALKALINE. SMALL AMOUNT OF PROBENECID GLUCURONIDE APPEARS IN URINE.
... /ORG ACID CMPD SUCH AS PROBENECID /ARE/ NOT TAKEN UP SO AVIDLY BY /PARENCHYMATOUS OR RETICULO-ENDOTHELIAL TISSUES/ & EXHIBIT HIGHER PLASMA CONCN ... .
For more Absorption, Distribution and Excretion (Complete) data for PROBENECID (8 total), please visit the HSDB record page.

---

Metabolism / Metabolites
YIELDS P-DIPROPYLSULFAMOYLBENZOYL-BETA-D-GLUCURONIC ACID; P-(2-HYDROXYPROPYL N-PROPYLSULFAMOYL) BENZOIC ACID; P-(3-HYDROXYPROPYL N-PROPYLSULFAMOYL) BENZOIC ACID; & P-PROPYLSULFAMOYLBENZOIC ACID IN MAN. /FROM TABLE/
STRUCTURES OF ALL OF METAB OF PROBENECID IN RAT BILE & HUMAN URINE HAVE BEEN ELUCIDATED. PROPIONIC ACID HAS NOW BEEN IDENTIFIED AS ANOTHER PROBENECID METAB. MAJOR METABOLIC PATHWAYS INVOLVE SIDE-CHAIN OXIDATION & GLUCURONIDE CONJUGATION ... .
... BETA-GLUCURONIDES OF 2- & 3-HYDROXYLATED METAB & ACYL GLUCURONIDE OF PROBENECID PER SE HAVE NOW BEEN IDENTIFIED. ... THERE IS CONSIDERABLE SPECIES DIFFERENCE IN METABOLISM. IN RATS & MONKEYS OXIDATION IS FAVORED. ... IN DOGS CONJUGATION ... /IS/ MAJOR PATHWAY, WHEREAS IN MAN, OXIDATIVE ... PATHWAY ... IS AS IMPORTANT AS GLUCURONIDATION.
CHRONIC ADMIN OF DRUGS NOT ONLY STIMULATES METAB OF OTHER CMPD, BUT IN SOME INSTANCES PHARMACOLOGICAL OR TOXIC EFFECT OF A DRUG WHEN GIVEN CHRONICALLY, DIMINISHES, BECAUSE IT STIMULATES ITS OWN METABOLISM EXAMPLE OF DRUG THAT EXERT THIS EFFECT IN DOGS ... /IS/ ... PROBENECID ... .
For more Metabolism/Metabolites (Complete) data for PROBENECID (6 total), please visit the HSDB record page.

---

Biological Half-Life
6-12 hours
THE HALF-LIFE OF /PROBENECID/ IN PLASMA IS DOSE DEPENDENT AND VARIES FROM LESS THAN 5 HR TO MORE THAN 8 HR ... .
Following oral administration of 2 g of probenecid, plasma half-life of the drug ranges from 4-17 hr; the half-life decreases as the dose decreases from 2 g to 500 mg.

23662399 man TDLo oral 630 mg/kg/6W KIDNEY, URETER, AND BLADDER: PROTEINURIS; KIDNEY, URETER, AND BLADDER: CHANGES PRIMARILY IN GLOMERULI Archives of Pathology., 94(241), 1972 [PMID:5051645]
23662399 mouse LD50 oral 1666 mg/kg BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; BEHAVIORAL: TETANY; LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES Journal of Pharmacology and Experimental Therapeutics., 102(208), 1951 [PMID:14851208]
23662399 rat LD50 intraperitoneal 394 mg/kg BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; BEHAVIORAL: TETANY; LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES Journal of Pharmacology and Experimental Therapeutics., 102(208), 1951 [PMID:14851208]
23662399 rabbit LD50 intravenous 304 mg/kg BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; BEHAVIORAL: TETANY; LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES Journal of Pharmacology and Experimental Therapeutics., 102(208), 1951 [PMID:14851208]
23662399 mouse LD50 subcutaneous 1156 mg/kg BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; BEHAVIORAL: TETANY; LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES Journal of Pharmacology and Experimental Therapeutics., 102(208), 1951 [PMID:14851208]

---

Hepatotoxicity
There are no reports on the frequency of liver test abnormalities during probenecid therapy, but they are probably rare as the drug is largely secreted unchanged in the urine. A single case report of a severe hypersensitivity reaction from probenecid and rechallenge with a rapid and severe recurrence of jaundice was reported over 50 years ago. As is typical for hypersensitivity reactions, the onset was within days of starting probenecid and was accompanied by fever and rash.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal doses of probenecid up to 2 grams daily produce low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. In animal studies, probenecid increased the breastmilk excretion of cimetidine, possible via an interaction with an active transport mechanism in the breast. The implications of enhanced excretion of drugs given with probenecid for nursing mothers and their infants has not been studied; however, only a few drugs are known to undergo active transport into breastmilk.
◉ Effects in Breastfed Infants
A woman with mastitis received 3 days of intravenous cephalothin, followed by 16 days of probenecid 500 mg and cephalexin 500 mg 4 times daily for 16 days. Her infant developed green liquid stools, severe diarrhea, discomfort and crying. The authors judged the effects to be probably related to the cephalothin and cephalexin in milk rather than the probenecid.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
75-95%

[1]. Probenecid: novel use as a non-injurious positive inotrope acting via cardiac TRPV2 stimulation. J Mol Cell Cardiol. 2012 Jul;53(1):134-44.

[2]. Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol Pharmacol. 2000 Apr;57(4):760-8.

[3]. Probenecid inhibits the human bitter taste receptor TAS2R16 and suppresses bitter perception of salicin. PLoS One. 2011;6(5):e20123.

[4]. Probenecid, a gout remedy, inhibits pannexin 1 channels. Am J Physiol Cell Physiol. 2008 Sep;295(3):C761-7.

Probenecid appears as odorless white or almost white crystalline powder. Slightly bitter taste; pleasant aftertaste. (NTP, 1992)
Probenecid is a sulfonamide in which the nitrogen of 4-sulfamoylbenzoic acid is substituted with two propyl groups. It has a role as a uricosuric drug. It is a sulfonamide and a member of benzoic acids.
The prototypical uricosuric agent. It inhibits the renal excretion of organic anions and reduces tubular reabsorption of urate. Probenecid has also been used to treat patients with renal impairment, and, because it reduces the renal tubular excretion of other drugs, has been used as an adjunct to antibacterial therapy.
Probenecid is a uricosuric agent used for the treatment of gout usually in combination with other agents. Probenecid has been associated with minor serum aminotransferase elevations and very rarely with hypersensitivity reactions which, even more rarely, can be accompanied by acute liver injury.
Probenecid is a benzoic acid derivative with antihyperuricemic property. Probenecid competitively inhibits the active reabsorption of urate at the proximal tubule in the kidney thereby increasing urinary excretion of uric acid and lowering serum urate concentrations. This prevents urate deposition and promotes resolution of existing urate deposits. In addition, probenecid modulates the transport of organic acids and acidic drugs at the proximal and distal renal tubule, thereby increasing the drug serum concentration.
The prototypical uricosuric agent. It inhibits the renal excretion of organic anions and reduces tubular reabsorption of urate. Probenecid has also been used to treat patients with renal impairment, and, because it reduces the renal tubular excretion of other drugs, has been used as an adjunct to antibacterial therapy.
See also: Colchicine; probenecid (component of); Ampicillin/ampicillin trihydrate; probenecid (component of).

---

Drug Indication
For the reduction of serum uric acid concentrations in chronic gouty arthritis and tophaceous gout in patients with frequent disabling gout attacks. Has also been effectively used to promote uric acid excretion in hyperuricemia secondary to the administration of thiazide and related diuretics.

---

Mechanism of Action
Probenecid inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Probenecid may also reduce plasma binding of urate and inhibit renal secretion of uric acid at subtherapeutic concentrations. The mechanism by which probenecid inhibits renal tubular transport is not known, but the drug may inhibit transport enzymes that require a source of high energy phosphate bonds and/or nonspecifically interfere with substrate access to protein receptor sites on the kidney tubules.
IN HIGHER DOSES THAN ARE REQUIRED FOR URICOSURIC EFFECT, PROBENECID ALSO INHIBITS TRANSPORT OF ORG ACIDS AT OTHER SITES, IE, TRANSPORT SYSTEM THAT REMOVES ORG ACIDS FROM CEREBROSPINAL FLUID.
IT INHIBITS TUBULAR REABSORPTION OF URATE, THUS INCR URINARY EXCRETION OF URIC ACID & DECR SERUM URIC ACID LEVELS.
Probenecid is a renal tubular blocking agent. The drug competitively inhibits active reabsorption of uric acid at the proximal convoluted tubule, thus promoting urinary excretion of uric acid and reducing serum urate concentrations. Probenecid may reduce plasma protein binding of urate and, in subtherapeutic doses, may inhibit renal secretion of uric acid. In healthy individuals, probenecid has no effect on the glomerular filtration rate or on the tubular reabsorption of normal urinary constituents such as glucose, arginine, urea, sodium, potassium, chloride, or phosphate.
At the proximal and distal tubules, probenecid competitively inhibits the secretion of many weak organic acids including penicillins, most cephalosporins, and some other beta-lactam antibiotics. In general, the net effect of probenecid on the plasma concentration of weak acids depends on the ratio of the amount of organic acid secreted by the kidneys to that amount filtered at the glomeruli. Thus, probenecid substantially increases plasma concentrations of acidic drugs eliminated principally by renal secretion, but increases plasma concentrations only slightly if the drug is eliminated mainly by filtration. Plasma concentrations of penicillins are often more than doubled by probenecid; the concentration of penicillin in the CSF is also increased. Probenecid also substantially increases plasma concentrations of most cephalosporins and some other beta-lactam antibiotics. In addition, half-lives of the penicillins and cephalosporins are prolonged and their volumes of distribution may be reduced by probenecid. ... The cellular mechanism(s) responsible for the inhibition of renal tubular transport by probenecid is not known. The drug may inhibit transport enzymes that require a source of high energy phosphate bonds and/or nonspecifically interfere with substrate access to protein receptor sites on the kidney tubules.
CSF concentrations of 5-hydroxyindoleacetic acid, homovanillic acid, cyclic adenosine monophosphate, and 4-hydroxy-3-methoxyphenylglycol are elevated following administration of probenecid. It has been proposed that probenecid blocks the active transport of these organic acids from the CSF into blood. Probenecid-induced elevations of homovanillic acid (a dopamine metabolite) in the CSF of patients with parkinsonian syndrome and of 5-hydroxyindoleacetic acid(a metabolite of serotonin) in the CSF of mentally depressed patients are substantially lower than those in healthy patients.

C13H18NNAO4S

307.34

307.08542

23795-03-1

Probenecid-d14;1189657-87-1;Probenecid;57-66-9;Probenecid-d7;2012598-90-0

23662399

White to off-white solids at room temperature

438ºC at 760mmHg

218.7ºC

1.91E-08mmHg at 25°C

1.942

85.89

5

7

20

380

0

[Na+].CCCN(S(C1C=CC(C([O-])=O)=CC=1)(=O)=O)CCC

QCCCFHDTBTUDEA-UHFFFAOYSA-M

InChI=1S/C13H19NO4S.Na/c1-3-9-14(10-4-2)19(17,18)12-7-5-11(6-8-12)13(15)16;/h5-8H,3-4,9-10H2,1-2H3,(H,15,16);/q;+1/p-1

sodium 4-(dipropylsulfamoyl)benzoate

Probenesulfonate; Probenecid sodium; 23795-03-1; Sodium probenecid; Benemid, sodium salt; Probenecid sodium salt;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

---

注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

View More

注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

---

口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

View More

口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

---

注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。