HSV-1 (IC50 = 2.9 μg/mL)

Valaciclovir (VACV) has maximal rates of 23.34 nmol/mg protein/5 minutes and 1.64 mM, respectively, according to Michaelis-Menten constants, with concentration-dependent and saturable absorption. The Km values in rat, rabbit, and Caco-2 cells, as well as in hPEPT1/CHO cells, were quite similar, suggesting that hPEPT1 controls the in vitro intestinal transport characteristics of VACV [5].

A major comparative trial found that valacyclovir (1 g twice day) for 10 days was just as effective as acyclovir (200 mg 5 times daily) for treating a first bout of genital herpes. Two trials found that valacyclovir (200 mg five times daily) was equally efficacious as acyclovir (200 mg five times daily) in a five-day treatment cycle for managing relapses. Valacyclovir at a dose of 1 g per day works just as well as 2 g per day. One dose of valacyclovir can be given every day [1]. Serum and cerebrospinal fluid acyclovir concentrations were assessed at steady state following six days of oral valacyclovir 1,000 mg three times a day [2]. PE and AC have EC50 values in 3T3 cells of 0.02 and 0.01 ug/ml, however in BHK cells they are 0.2 and 0.03 ug/ml. Immunosuppressed mice that were infected were treated with FA and VA (bid, 5.5 days) to eradicate otoparesis, ear lesions (vesicles, etc.), and death. The percentage of erythema was also reduced from 100% to 24% and 38%. By day six, the virus had vanished from the ears and brainstem, but in mice receiving VA treatment, it returned when the medication was stopped [3].

The in vitro 50% inhibitory concentration (IC50) of HSV-1 W strain was determined by using a plaque-reduction assay to verify its sensitivity to acyclovir. The IC50 for HSV-1 W was determined to be 2.9 µg/ml. [4].

The results of previous work performed in our laboratory using an in situ perfusion technique in rats and rabbit apical brush border membrane vesicles have suggested that the intestinal uptake of valacyclovir (VACV) appears to be mediated by multiple membrane transporters. Using these techniques, it is difficult to characterize the transport kinetics of VACV with each individual transporter in the presence of multiple known or unknown transporters. The purpose of this study was to characterize the interaction of VACV and the human intestinal peptide transporter using Chinese hamster ovary (CHO) cells that overexpress the human intestinal peptide transporter (hPEPT1) gene. VACV uptake was significantly greater in CHO cells transfected with hPEPT1 than in cells transfected with only the vector, pcDNA3. The optimum pH for VACV uptake was determined to occur at pH 7.5. Proton cotransport was not observed in hPEPT1/CHO cells, consistent with previously observed results in tissues and Caco-2 cells. VACV uptake was concentration dependent and saturable with a Michaelis-Menten constant and maximum velocity of 1.64 +/- 0.06 mM and 23.34 +/- 0.36 nmol/mg protein/5 min, respectively. A very similar Km value was obtained in hPEPT1/CHO cells and in rat and rabbit tissues and Caco-2 cells, suggesting that hPEPT1 dominates the intestinal transport properties of VACV in vitro. VACV uptake was markedly inhibited by various dipeptides and beta-lactam antibiotics, and Ki values of 12.8 +/- 2.7 and 9.1 +/- 1.2 mM were obtained for Gly-Sar and cefadroxil at pH 7.5, respectively. The present results demonstrate that VACV is a substrate for the human intestinal peptide transporter in hPEPT1/CHO cells and that although transport is pH dependent, proton cotransport is not apparent. Also, the results demonstrate that the hPEPT1/CHO cell system has use in investigating the transport kinetics of drugs with the human intestinal peptide transporter hPEPT1; however, the extrapolation of these transport properties to the in vivo situation requires further investigation[5].

Acyclovir has been a frequently used antiviral agent in the clinical treatment of leukemia, acute encephalitis, malignant tumor and herpes simplex. The adverse effects of this drug have been widely described in clinical practice. In the present study, a case of a 35-year-old female patient diagnosed with herpes simplex, who developed acute renal injury following treatment with valacyclovir hydrochloride, is described. Kidney biopsy, light microscopy and laboratory examination were performed, and all findings revealed the signs of evident vacuolar degeneration of capillary endothelial and renal tubular epithelial cells, erythrocyte aggregation in partial renal tubule and microvilli exfoliation from epithelial cells. Renal interstitial edema was clearly identified. The clinical evidence observed from this female patient indicated that renal functions should be closely monitored during valacyclovir hydrochloride administration. A variety of effective measures, such as hydration, alkalizing urine, promoting the discharge of medication and the use of antagonists are recommended following the administration of antiviral agents[1].

Absorption, Distribution and Excretion
Following oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and converted to acyclovir and L-valine. In 12 healthy subjects, after oral administration of 1 gram of valacyclovir and intravenous injection of 350 mg of acyclovir, the absolute bioavailability of acyclovir was measured to be 54.5% ± 9.1%. The bioavailability of acyclovir (a metabolite of valacyclovir) was not affected by food. In 4 healthy subjects, following a single oral administration of 1 gram of radiolabeled valacyclovir, 46% and 47% of the administered radioactivity were detected in urine and feces, respectively, within 96 hours. Acyclovir accounted for 89% of the radioactive material excreted in urine.
The cerebrospinal fluid (CSF) permeability (determined by the CSF/plasma AUC ratio) is approximately 25% for acyclovir and its metabolite 8-hydroxyacyclovir (8-OH-ACV), and approximately 2.5% for its metabolite 9-(carboxymethoxy)methylguanine. In a study of immunocompromised pediatric patients, the volume of distribution of valacyclovir at a dose of 15 ml/kg was 1.34 ± 0.65 L/kg.
Following a single 1-g valacyclovir dose in 12 healthy volunteers, the renal clearance of acyclovir was approximately 255 ± 86 mL/min, representing 42% of the total apparent plasma clearance of acyclovir.
After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and almost completely converted to acyclovir and L-valine via first-pass metabolism in the intestine and/or liver. In 12 healthy volunteers, the absolute bioavailability of acyclovir was 54.5% ± 9.1% after oral administration of 1 g valacyclovir and intravenous administration of 350 mg acyclovir. The bioavailability of acyclovir via valacyclovir (Valtrex) was not affected by food (873 kcal breakfast containing 51 g fat, taken 30 minutes later). The binding rate of valacyclovir to human plasma proteins ranged from 13.5% to 17.9%. The binding rate of acyclovir to human plasma proteins ranged from 9% to 33%. The pharmacokinetic distribution of acyclovir administered with valacyclovir was consistent with previous experience with intravenous and oral acyclovir. In 4 healthy subjects, following a single oral dose of 1 g of radiolabeled valacyclovir, 46% and 47% of the radioactive material were excreted in urine and feces, respectively, within 96 hours. Of the radioactive material excreted in urine, 89% was acyclovir. Following a single administration of 1 gvalacyclovir to 12 healthy volunteers, the renal clearance of acyclovir was approximately 255 ± 86 mL/min, representing 42% of the total apparent plasma clearance of acyclovir. The intestinal transport mechanism of valacyclovir, an L-valine ester prodrug of acyclovir, was investigated in rats using in situ intestinal perfusion. Results indicated that the oral bioavailability of valacyclovir appeared to be significantly affected by factors such as the conversion of valacyclovir to malabsorbable acyclovir before absorption; the involvement of multiple transport proteins in the absorption of valacyclovir in the small intestine; and the low permeability of valacyclovir in the colon. In 5 lactating women, after oral administration of 500 mg valacyclovir, the peak concentration (Cmax) of acyclovir in breast milk was 0.5 to 2.3 times the corresponding maternal serum acyclovir concentration (median 1.4 times). The AUC of acyclovir in breast milk is 1.4 to 2.6 times that in maternal serum (median 2.2 times). A maternal dose of 500 mg valacyclovir twice daily provides a nursing infant with approximately 0.6 mg/kg/day of oral acyclovir. This results in a nursing infant exposure that is less than 2% of the standard intravenous dose of acyclovir (30 mg/kg/day) given to newborns. Unmetabolized valacyclovir was not detected in maternal serum, breast milk, or infant urine.

---

Metabolism/Metabolites
Valacyclovir is first-pass metabolized in the intestine and/or liver to acyclovir and L-valine. Acyclovir is metabolized by alcohol dehydrogenases and aldehyde dehydrogenases, and a small amount is converted to an inactive metabolite by aldehyde oxidase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes.
…The major metabolite of acyclovir is 9-carboxymethoxymethylguanine. Valacyclovir undergoes first-pass metabolism in the intestine and/or liver to acyclovir and L-valine. A small amount of acyclovir is converted to inactive metabolites by aldehyde oxidase and alcohol-aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Unconverted valacyclovir plasma concentrations are low and transient, usually unquantifiable within 3 hours after administration. Peak plasma concentrations of valacyclovir are typically below 0.5 μg/mL at all doses. After a single dose of 1 g valacyclovir, the mean plasma valacyclovir concentrations in patients with hepatic impairment, renal insufficiency, and healthy volunteers concurrently taking cimetidine and probenecid were 0.5, 0.4, and 0.8 μg/mL, respectively.

---

Biological Half-Life
In multiple valacyclovir studies in volunteers with normal renal function, the plasma elimination half-life of acyclovir typically ranged from 2.5 to 3.3 hours.
In all valacyclovir studies in volunteers with normal renal function, the plasma elimination half-life of acyclovir typically ranged from 2.5 to 3.3 hours.

Hepatotoxicity
Oral valacyclovir treatment is associated with a low incidence of mild to moderate elevations in serum transaminases, but these abnormalities are usually asymptomatic and resolve spontaneously even with continued treatment. However, because enzyme elevations are not uncommon during varicella-zoster virus infection (including chickenpox and shingles) and can progress to clinically manifested hepatitis or even acute liver failure, it is difficult to attribute liver dysfunction to valacyclovir treatment. Clinically manifested liver disease caused by valacyclovir itself is rare, but case reports exist. Case 1 had a short onset time (1 to 2 weeks), a mild course, few symptoms, and rapid resolution. The described liver injury pattern was mixed hepatocellular-cholestatic. No immune hypersensitivity features or autoantibodies were found. Probability score: D (likely a rare cause of clinically manifested liver injury).

---

Effects during pregnancy and lactation
◉ Overview of use during lactation
After valacyclovir administration, the dose of acyclovir in breast milk is less than 1% of the typical infant dose, and no adverse effects are expected on breastfed infants. No special precautions are required for the use of valacyclovir during lactation. One study showed that valacyclovir administration to mothers co-infected with herpes simplex virus type 2 and HIV reduced HIV shedding in breast milk at 6 and 14 weeks postpartum, but this effect was not observed thereafter. [1] In another study of HIV-positive mothers, valacyclovir did not reduce cytomegalovirus (CMV) shedding in breast milk or the risk of CMV infection in infants. [2]
◉ Effects on breastfed infants
In a study of pregnant women co-infected with HIV and herpes simplex virus, the mothers received 300 mg of zidovudine daily from week 34 of pregnancy to 12 months postpartum and nevirapine at delivery. Half of the women (n = 74) received 500 mg valacyclovir orally twice daily from 34 weeks of gestation to 12 months postpartum. At 6 weeks postpartum, all infants who received acyclovir via breast milk had normal serum creatinine levels (<0.83 mg/dL). Except for one infant with an ALT level of 70.1 units/L, the median serum creatinine and alanine aminotransferase (ALT) levels, as well as growth and development, were not different from those of infants who had not been exposed to valacyclovir. Infants whose mothers received valacyclovir generally experienced similar adverse reactions to those in the placebo group, but the treated infants had a lower risk of eczema and thrush than the placebo group. [1][4]
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

---

Protein binding
Valacyclovir had low binding rates to human plasma proteins, ranging from 13.5% to 17.9%.

---

Interactions
Valacyclovir co-administration with probenecid may increase the peak plasma concentration and AUC of acyclovir. This pharmacokinetic interaction is not clinically significant in patients with normal renal function, therefore no dose adjustment is required.
Valacyclovir co-administration with cimetidine may increase the peak plasma concentration and AUC of acyclovir. This pharmacokinetic interaction is not clinically significant in patients with normal renal function, therefore no dose adjustment is required.
Mycophenolate mofetil (MMF) is a drug that can reduce the incidence of kidney transplant rejection. However, cytomegalovirus infection is a common complication of this treatment, so doctors often prescribe antiviral prophylaxis drugs such as valacyclovir. Neutropenia may occur during this combination therapy, but the cause of this adverse reaction is difficult to determine. This report presents a case of neutropenia in a woman receiving MMF and valacyclovir treatment. Because the duration of valacyclovir treatment perfectly coincided with the duration of neutropenia, and the mycophenolate mofetil trough concentration increased with rising neutrophil counts, neutropenia was initially thought to be caused by valacyclovir. However, after reviewing case reports of neutropenia in the literature, an interaction between mycophenolate mofetil and valacyclovir is suspected. Mycophenolate mofetil may increase intracellular valacyclovir concentrations to hematologic toxic levels. This mechanism may explain the interaction between the two, but further research is needed to confirm it.

[1]. Valacyclovir. New indication: for genital herpes, simpler administration. Can Fam Physician. 1999 Jul;45:1698-700, 1703-5.

[2]. Acyclovir levels in serum and cerebrospinal fluid after oral administration of valacyclovir. Antimicrob Agents Chemother. 2003 Aug;47(8):2438-41.

[3]. Comparison of efficacies of famciclovir and valaciclovir against herpes simplex virus type 1 in a murineimmunosuppression model. Antimicrob Agents Chemother. 1995 May;39(5):1114-9.

[4]. Dhaliwal DK, Romanowski EG, Yates KA, Valacyclovir inhibits recovery of ocular HSV-1 after experimental reactivation by excimer laser keratectomy. Cornea. 1999 Nov;18(6):693-9.

[5]. Guo A, Hu P, Balimane PV, Interactions of a nonpeptidic drug, valacyclovir, with the human intestinal peptide transporter (hPEPT1) expressed in a mammalian cell line.J Pharmacol Exp Ther. 1999 Apr;289(1):448-54.

Therapeutic Uses
Antiviral Drugs
Oral valacyclovir is used to treat cases of initial infection with genital herpes simplex virus (HSV-2) in immunocompetent adults and adolescents. Because many patients with initial genital herpes infection experience mild clinical symptoms that later develop into severe or prolonged symptoms, the Centers for Disease Control and Prevention (CDC) states that most patients with initial genital herpes infection should receive antiviral treatment. /US Product Label Includes/
Oral valacyclovir is used to treat cases of recurrent genital herpes in immunocompetent adults and adolescents. Antiviral treatment for recurrent genital herpes can be administered intermittently to reduce or shorten the course of the disease, or continuously as a suppressive therapy to reduce the frequency of recurrences. /US Product Label Includes/
Valacyclovir is used to treat intermittent outbreaks of cold sores (perioral herpes, labial herpes, vesicular herpes) in adults and adolescents. /US Product Label Includes/
For more complete data on the therapeutic uses of valacyclovir (out of 9), please visit the HSDB record page.

---

Drug Warning
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) has occurred in patients with advanced HIV-1 infection and allogeneic bone marrow and kidney transplant recipients in clinical trials of valacyclovir (8 g daily), with some cases even resulting in death. If clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur, valacyclovir should be discontinued immediately.

There are currently no adequate and well-controlled studies on the use of valacyclovir or acyclovir in pregnant women. Based on prospective pregnancy registry data from 749 pregnancies, the overall incidence of birth defects in infants exposed to acyclovir in utero appears to be similar to that in the general population. Valacyclovir should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus.

Acute renal failure has been reported in the following situations: 1. Elderly patients, regardless of renal impairment. Caution should be exercised when using valacyclovir in elderly patients, and dose reduction is recommended for patients with impaired renal function.
2. Patients with underlying kidney disease who are receiving a dose of valacyclovir higher than the recommended dose for their renal function level. A dose reduction of valacyclovir is recommended for patients with impaired renal function. 3. Patients taking other nephrotoxic medications. Caution should be exercised when using valacyclovir in patients taking potentially nephrotoxic medications. 4. Patients who are not adequately hydrated. Acyclovir may precipitate in the renal tubules when the solubility of acyclovir in the tubular fluid (2.5 mg/mL) exceeds its solubility. All patients should maintain adequate hydration.
The most common adverse reactions occurring in more than 10% of adult patients treated with valacyclovir for at least one indication and more common than placebo are headache, nausea, and abdominal pain. The only reported adverse reaction occurring in more than 10% of pediatric patients under 18 years of age is headache.
For more complete data on drug warnings for valacyclovir (8 of 8), please visit the HSDB record page. Pharmacodynamics Antibacterial Effects Valacyclovir exhibits varying degrees of inhibition against herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). The quantitative relationship between the sensitivity of herpesviruses to antiviral drugs in cell culture and clinical response to the same antiviral therapy in humans has not been elucidated. Sensitivity test results, described as the drug concentration required to inhibit viral growth by 50% in cell culture (EC50), can vary considerably due to various factors. Clinical Study Results The following is a summary of clinical study results for various diseases: _Herpes labialis_ Immunocompromised patients with herpes labialis were observed using either a 1-day course (2 g valacyclovir twice daily for 1 day, followed by a placebo for 1 day) or a 2-day course (2 g valacyclovir twice daily for 2 consecutive days). Compared to the placebo group, the treatment group had a shortened mean duration of cold sore throat flare-ups by approximately one day. A two-day course of valacyclovir did not show superior efficacy compared to a one-day course. No clinically significant difference was observed between the valacyclovir and placebo groups in preventing post-papular progression of cold sore throat lesions, suggesting that the timing of valacyclovir administration is an important consideration. First Genital Herpes Outbreak: A double-blind trial randomized 643 immunocompetent adult patients who presented with their first genital herpes symptoms within 72 hours of symptom onset. Patients were randomly assigned to receive either 10 days of valacyclovir treatment (1 g twice daily, n=323) or oral acyclovir (200 mg five times daily, n=320). The median time to healing of herpes lesions was 9 days in both groups, the median time to pain relief was 5 days, and the median time to viral shedding was approximately 3 days. _Recurrent Genital Herpes_ Results from three independent studies showed that patients receiving a 3- to 5-day course of valacyclovir recovered on average in 4 days, experienced relief of lesion-related pain in 2 to 3 days, and stopped viral shedding on average in 2 days. These results indicate that valacyclovir treatment is significantly more effective than placebo. Regarding Drug Resistance Resistance to acyclovir in herpes simplex virus and varicella-zoster virus may stem from qualitative and quantitative changes in viral thymidine kinase (TK) and/or DNA polymerase. Clinical isolates of varicella-zoster virus (VZV) with reduced susceptibility to acyclovir have been isolated from HIV patients. A total of 522 TK-deficient VZV mutant strains were identified in these cases.

C13H20N6O4

324.341

324.154

C, 48.14; H, 6.22; N, 25.91; O, 19.73

124832-26-4

Valacyclovir hydrochloride;124832-27-5;Valacyclovir hydrochloride hydrate;1218948-84-5

135398742

Typically exists as solid at room temperature

1.5±0.1 g/cm3

170-172

309.7ºC

1.673

-0.88

3

7

8

23

483

1

N[C@@H](C(C)C)C(OCCOCN1C=NC2=C1N=C(N)NC2=O)=O

HDOVUKNUBWVHOX-QMMMGPOBSA-N

InChI=1S/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1

2-((2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy)ethyl L-valinate

BW-256U87; BW-256; BW256256U87 hydrochloride; BW 256 Val-ACV; Valtrex; Zelitrex; Valacyclovir HCl; Valacyclovir hydrochloride; ValACV; Zelitrex; Valcivir; Valcyclovir; Val-ACV;

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

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)