Plasma Concentrations Of Acyclovir Research Articles

A simple method for the determination of acyclovir concentrations in human plasma using high-performance liquid chromatography

BackgroundAcyclovir is an anti-viral medication given to treat herpes simplex and herpes zoster infection. In some severe conditions such as herpes encephalitis, acyclovir is administered intravenously. However, high acyclovir doses may cause acute kidney injury and low acyclovir dose may predispose the patient to inadequate exposure to acyclovir which could be fatal in some conditions. In such cases, the acyclovir plasma concentrations will potentially guide the diagnosis and management of the kidney injury. In this study, we provide a simple and time-efficient method for analyzing acyclovir in human plasma using high-performance liquid chromatography (HPLC).ResultsThe process starts with a single protein precipitation step by adding acetonitrile to deproteinize 300 µL of plasma. The chromatographic separation conditions consist of a mobile phase of water: methanol (97:3, v/v), a flow rate of 1 mL/min, a run time of 17 min, and a detection wavelength of 254 nm. The calibration curve was linear over the range of (0.70–60 mg/L) (r2 ˃ 0.99). The retention times of acyclovir and the internal standard were around 15 and 12 min, respectively. The intra-day and inter-day analysis of acyclovir in plasma using this method exhibited accuracy and precision of less than 7%, which lies within the acceptable range. Different greenness assessment tools confirmed that the proposed method is eco-friendly.ConclusionThe proposed method of analysis of acyclovir in the plasma using HPLC is simple, green and accurate method. This method could be applied in clinical settings where monitoring acyclovir concentrations is essential as it has wide range of the concentrations that could be detected.

Comparison of dosing strategies in obese patients prescribed intravenous acyclovir and evaluation of rate of acute kidney injury

IntroductionThere is limited guidance on the most appropriate dosing strategy for intravenous (IV) acyclovir in obese patients. The manufacturer's labelling suggests using ideal body weight (IBW); however, previous pharmacokinetic studies of obese patients have shown more rapid systemic clearance and lower area under the curve and peak concentrations compared with patients with a body mass index (BMI) < 30 kg/m2. Although pharmacokinetic data suggest that plasma concentrations of acyclovir are best predicted when using adjusted body weight (AdjBW) doses, there is concern about higher rates of acute kidney injury (AKI). MethodsThis was a retrospective cohort review of adult patients with a BMI ≥ 30 kg/m2 prescribed IV acyclovir ≥ 48 hours between 1 January 2014 and 31 August 2021 at a 511-bed academic medical centre. The primary objective was to compare AdjBW with IBW dosing in obese patients who had been prescribed IV acyclovir and to determine whether AdjBW dosing results in higher rates of AKI. ResultsNinety-four patients were included: 61 were in the IBW cohort and 33 were in the AdjBW cohort. The median BMI [IQR] for all patients was 34.7 kg/m2 [31.8–40.6]. Patients in the AdjBW cohort received a significantly higher median acyclovir dose of 800 mg/dose [IQR 700–850] compared with 600 mg/dose [IQR 500–700] for the IBW cohort (P ≤ 0.0001). No patients dosed using AdjBW developed AKI compared with eight (13.1%) in the IBW group. ConclusionIn this study, 8.5% of all obese patients receiving acyclovir developed AKI. Further studies are needed to confirm dosing recommendations.

Effect of benzylpenicillin on intravenous pharmacokinetics of acyclovir in red-eared slider turtles (Trachemys scripta elegans).

The aim of this study was to determine the effect of benzylpenicillin on the pharmacokinetics of acyclovir in red-eared slider turtles (Trachemys scripta elegans). Six clinically healthy red-eared slider turtles weighing 400 and 580g were used for the study. Acyclovir (40mg/kg) and benzylpenicillin (30mg/kg) were administered intravenously to turtles. In the study, the cross-pharmacokinetic design (2×2) with a 30-day washout period was performed in two periods. Plasma concentrations of acyclovir were assayed using the high-performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated by two-compartment open pharmacokinetic model. Following the administration of acyclovir alone, elimination half-life (t1/2 β ), area under the plasma concentration-time curve (AUC), total clearance (ClT ), and volume of distribution at steady-state (Vdss ) were 20.12hr, 1,372hr*µg/mL, 0.03 Lhr-1 kg-1 , and 0.84 L/kg, respectively. Benzylpenicillin administration increased t1/2 β , AUC, and Vdss while decreased ClT of acyclovir. These results showed that benzylpenicillin changed the pharmacokinetics of acyclovir following simultaneous administration in turtles. However, further research is needed to determine molecular mechanism of interaction in turtle.

Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2.

Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF’s active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5−100 μmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC50 value of 4.91 μmol/L. TER (5 μmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells’ uptake of acyclovir and increased the plasma concentration.

Comparison of Intrathecal Concentrations of Acyclovir following Epidural and Intravenous Administration in Rats

Background: Herpes zoster is a disease caused by reactivation of varicella-zoster virus in sensory cranial nerves and dorsal root ganglion. Our presumption was that epidural administration of acyclovir near the viral burden could be more advantageous than intravenous (IV) administration. The cerebrospinal fluid (CSF) concentration of acyclovir after epidural administration was determined to be higher than that after IV administration in rats. Objective: In this study, we tested the hypothesis that the concentration of acyclovir in CSF after epidural administration is higher than that achieved after IV administration in rats. Study Design: A randomized controlled animal trial. Methods: A total of 30 adult male Sprague-Dawley rats were used. The rats were randomly divided into 2 equal groups, epidural (Group Epi) and IV (Group IV) administration groups (n = 15). Group Epi was further subdivided into 3 groups according to acyclovir dosage; each group comprised 5 animals receiving injections at dosages of 0.3 mg, 0.6 mg, and 0.9 mg. Group IV was also subdivided into 3 groups receiving dosages of 3 mg, 6 mg, and 9 mg. We measured CSF and plasma acyclovir concentrations one hour after administration. Results: In Group Epi, the median plasma concentrations of acyclovir were lower than that in CSF (P &lt; 0.05). In Group IV, the median plasma concentrations of acyclovir were significantly higher than that in CSF (P &lt; 0.05). The CSF concentrations of acyclovir in Group Epi were significantly higher than that in Group IV (P &lt; 0.05). The plasma concentrations of acyclovir in Group Epi were significantly lower than that in Group IV (P &lt; 0.05). Limitations: There were no references of equivalent dosages of acyclovir between IV and epidural administration. However, it is obvious in this study that epidural administration of a low dose of acyclovir can more effectively increase its concentration in the intrathecal space than IV administration. Conclusions: Epidural administration of acyclovir provides superior drug concentrations in the intrathecal space compared to IV administration. Key words: Acyclovir, epidural injection, herpes zoster, varicella zoster virus

Acyclovir Entrapped N-Trimethyl Chitosan Nanoparticles for Oral Bioavailability Enhancement

Objective: The aim of the study was to evaluate a nanoparticulate system composed of Ntrimethyl chitosan (TMC) for improving the oral bioavailability of Acyclovir (ACV). Methods: TMC was prepared by methylation of chitosan and characterized by H-NMR spectroscopy. The ionic gelation method was used to prepare ACV loaded TMC nanoparticles. Non-everted sac technique was used to assess ex vivo permeation in rats. A pharmacokinetic study of the optimized formulation was carried out in male Wistar rats in comparison with ACV alone. Results: Ex vivo studies exhibited a significant rise in the permeation of ACV from the rat intestinal membrane when formulated as nanoparticles. The results showed an increase in plasma concentration of ACV from the nanoformulation and significant difference (p < 0.05) in pharmacokinetic parameters as compared to pure drug, ACV. Conclusion: The results suggest that higher oral delivery of ACV can be achieved by combining the benefits of both TMC and nanoparticles.

Development and optimisation of mucoadhesive nanoparticles of acyclovir using design of experiments approach

The aim of our study was to improve the bioavailability of acyclovir (ACV) by delivery of mucoadhesive nanoparticles (NPs) and controlled delivery of drug at its absorption window. Central composite design was used by which the effects of independent variables (gelatin and Pluronic F-68) on various responses such as particle size, polydispersity index, entrapment efficiency, loading efficiency, drug release and mucoadhesive strength were studied. The optimised formulation was evaluated for morphology, stability, pharmacokinetic and gastrointestinal tracking. The optimised NPs were found to be nearly spherical. Changes in characteristics of NPs were not significant after six months of accelerated stability studies. In vivo mucoadhesion study showed significant retention of mucoadhesive NPs in upper gastro-intestinal tract for more than 12 h. Pharmacokinetic study in rats revealed that mucoadhesive NPs could maintain relatively steady plasma concentration of ACV for more than 10 h. The AUC0–∞ and mean residence time of optimised formulation (7527.9 ng h/mL and 12.09 h) were significantly high than tablet dispersion (3841.13 ng h/mL and 7.97 h).

Parameterization of small intestinal water volume using PBPK modeling

To facilitate accurate predictions of oral drug disposition, mechanistic absorption models require optimal parameterization. Furthermore, parameters should maintain a biological basis to establish confidence in model predictions. This study will serve to calculate an optimal parameter value for small intestinal water volume (SIWV) using a model-based approach. To evaluate physiologic fidelity, derived volume estimates will be compared to experimentally-based SIWV determinations. A compartmental absorption and transit (CAT) model, created in Matlab-Simulink®, was integrated with a whole-body PBPK model, developed in PK-SIM 5.2®, to provide predictions of systemic drug disposition. SIWV within the CAT model was varied between 52.5mL and 420mL. Simulations incorporating specific SIWV values were compared to pharmacokinetic data from compounds exhibiting solubility induced non-proportional changes in absorption using absolute average fold-error. Correspondingly, data pertaining to oral administration of acyclovir and chlorothiazide were utilized to derive estimates of SIWV. At 400mg, a SIWV of 116mL provided the best estimates of acyclovir plasma concentrations. A similar SIWV was found to best depict the urinary excretion pattern of chlorothiazide at a dose of 100mg. In comparison, experimentally-based estimates of SIWV within adults denote a central tendency between 86 and 167mL. The derived SIWV (116mL) represents the optimal parameter value within the context of the developed CAT model. This result demonstrates the biological basis of the widely utilized CAT model as in vivo SIWV determinations correspond with model-based estimates.

Benzylpenicillin inhibits the renal excretion of acyclovir by OAT1 and OAT3

BackgroundAcyclovir is acyclic guanosine derivative. Benzylpenicillin (PCG) is a β-lactam antibiotic. The purpose of this study was to investigate the pharmacokinetic drug-drug interaction (DDI) between PCG and acyclovir. MethodWhen acyclovir and PCG were co-administered, plasma concentration of acyclovir, urinary excretion of acyclovir in vivo, uptake of acyclovir in kidney slices and uptake of acyclovir in human (h) OAT1/hOAT3- HEK293 cells were determined to examine the effect of PCG on urinary excretion of acyclovir. ResultsThe plasma concentration of acyclovir was increased markedly and accumulative renal excretion and renal clearance of acyclovir were decreased significantly after intravenous administration of acyclovir in combination with PCG. PCG could decrease the uptake of acyclovir in kidney slices and in hOAT1-/hOAT3-human embryonic kidney (HEK293) cells. ConclusionsIt indicates that acyclovir is a substrate for OAT1 and OAT3. PCG inhibits the renal excretion of acyclovir by inhibiting renal transporters OAT1 and OAT3 in vivo and in vitro. These results suggest important information for DDI between PCG and acyclovir in kidney.

Inhibitory effect of JBP485 on renal excretion of acyclovir by the inhibition of OAT1 and OAT3

The purpose is to investigate whether the targets of drug-drug interactions (DDIs) between JBP485 and acyclovir are OAT1 and OAT3 in kidney. Plasma concentration and accumulative urinary excretion of acyclovir in vivo, uptake of acyclovir in kidney slices and uptake of acyclovir in human (h) OAT1/ hOAT3-human embryonic kidney (HEK) 293 cells in vitro were performed to examine the effect of JBP485 on urinary excretion of acyclovir. The plasma concentration of acyclovir was increased markedly and accumulative urinary excretion and renal clearance of acyclovir were decreased significantly after intravenous administration of acyclovir in combination with JBP485. JBP485 (a substrate for OAT1 and OAT3), p-aminohippurate (PAH) (a substrate for OAT1) and benzylpenicillin (PCG) (a substrate for OAT3) could decrease the uptake of acyclovir in kidney slices and in hOAT1-/hOAT3-HEK293 cells. These results suggest that JBP485 inhibits the renal excretion of acyclovir by inhibiting renal transporters OAT1 and OAT3 in vivo and in vitro. Our results indicate the possibility of DDI between dipeptide and acyclovir.

Bioavailability of Two Different Coated-Tablet Formulations of Valacyclovir of Two Different Strengths (500 mg and 1000 mg) in Healthy Mexican Adult Volunteers

Valacyclovir is a prodrug of acyclovir. In Mexico, it is indicated for the treatment of herpes zoster and herpes simplex infections. The aims of these 2 studies were to compare the bioavailability and to determine the bioequivalence of 2- test formulations containing 500 mg and 1000 mg of oral valacyclovir. Two separate, single-dose, open-label, randomized, 2-period, crossover studies were conducted. For each study a different set of 26 subjects of both genders was enrolled, with a 7-day washout period. In both studies, the study formulations were administered after a 10-hour overnight fast. For pharmacokinetic analysis, blood samples were drawn at baseline, 0.25, 0.50, 0.75, 1, 1.25, 1.50, 1.75, 2, 3, 4, 6, 8, 12 and 24 hours after administration. Plasma concentrations of acyclovir were determined using HPLC coupled to a fluorescence detector. The test and reference formulations were to be considered bioequivalent if the 90% CI for the geometric mean test/reference ratios were within a predetermined range of 80% to 125%. In the study with valacyclovir 500 mg, the 90% CI were 95.24% - 115.33% for Cmax, 96.20% - 103.55% for AUC0-t, 97.12% - 104.34% for AUC0-∞. In the study with valacyclovir 1000 mg the 90% CI were 86.22%- 100.87% for Cmax, 89.11% - 98.50% for AUC0-t, 89.00% - 98.34% for AUC0-∞. In both studies, a single dose of the test formulation met the regulatory requirements to assume bioequivalence, based on the rate and extent of absorption.

Pharmacokinetics and bioequivalence study of valacyclovir hydrochloride capsules after single dose administration in healthy Chinese male volunteers

The aim of the present study was to compare the bioavailability of valacyclovir (CAS 124832-26-4; INN: valaciclovir) from two valacyclovir hydrochloride (CAS 214832-27-5) capsules (150 mg/capsule as test preparation and 150 mg/capsule commercially available original capsule of the drug as reference preparation) in 20 Chinese healthy male volunteers, aged between 20 and 27. The study was conducted according to an open, randomized, single blind, 2-way crossover study design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 24 h post-dose. Valacyclovir hydrochloride is rapidly converted to acyclovir (CAS 59277-89-3) after oral administration, so the pharmacokinetics and bioequivalence of valacyclovir hydrochloride can be studied by determining the plasma concentration of acyclovir. Plasma concentrations of acyclovir were determined with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The pharmacokinetic parameters of test and reference formulations were estimated as follows: the maximum plasma concentrations (C(max)) were 2.04 +/- 0.43 microg/mL and 2.01 +/- 0.50 microg/mL; the median T(max) were 1.1 +/- 0.3 h and 1.0 +/- 0.3 h; plasma elimination half-lives (t1/2) were 2.94 +/- 0.42 h and 2.85 +/- 0.28 h. Values of AUC(0-t) demonstrate nearly identical bioavailability of valacyclovir hydrochloride from the examined formulations. AUC(0-15) were 6.70 +/- 1.26 microg x h/ mL and 6.96 +/- 1.25 microg x h/mL. Areas under the plasma concentration-time curve (AUC(0-infinity)) were 6.90 +/- 1.30 microg x h/mL and 7.15 +/- 1.31 microg x h/mL. Both primary target parameters, AUC(0-infinity) and AUC(0-t) were tested parametrically by analysis of variance (ANOVA) and relative bioavailabilities were 96.69 +/- 7.89% for AUC(0-infinity), 96.40 +/- 8.0% for AUC(0-15). Bioequivalence between test and reference preparation was demonstrated for both parameters, AUC(0-infinity) and AUC(0-t). The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80-125%. It meant that the test formulation was bioequivalent to the reference formulation for valacyclovir hydrochloride.

Mucoadhesive Microspheres for Gastroretentive Delivery of Acyclovir: In Vitro and In Vivo Evaluation

The aim of the present investigation was to evaluate the potential use of mucoadhesive microspheres for gastroretentive delivery of acyclovir. Chitosan, thiolated chitosan, Carbopol 71G and Methocel K15M were used as mucoadhesive polymers. Microsphere formulations were prepared using emulsion-chemical crosslinking technique and evaluated in vitro, ex-vivo and in-vivo. Gelatin capsules containing drug powder showed complete dissolution (90.5 +/- 3.6%) in 1 h. The release of drug was prolonged to 12 h (78.8 +/- 3.9) when incorporated into mucoadhesive microspheres. The poor bioavailability of acyclovir is attributed to short retention of its dosage form at the absorption sites (in upper gastrointestinal tract to duodenum and jejunum). The results of mucoadhesion study showed better retention of thiolated chitosan microspheres (8.0 +/- 0.8 h) in duodenal and jejunum regions of intestine. The results of qualitative and quantitative GI distribution study also showed significant higher retention of mucoadhesive microspheres in upper GI tract. Pharmacokinetic study revealed that administration of mucoadhesive microspheres could maintain measurable plasma concentration of acyclovir through 24 h, as compared to 5 h after its administration in solution form. Thiolated chitosan microsphere showed superiority over the other formulations as observed with nearly 4.0-fold higher AUC(0-24) value (1,090 +/- 51 ng h/ml) in comparison to drug solution (281 +/- 28 ng h/ml). Overall, the result indicated prolonged delivery with significant improvement in oral bioavailability of acyclovir from mucoadhesive microspheres due to enhanced retention in the upper GI tract.

MDR1 genotypes do not influence the absorption of a single oral dose of 600 mg valacyclovir in healthy Chinese Han ethnic males.

To investigate the influence of three single nucleotide polymorphisms (SNPs) in exon 12 (C1236T), exon 21 (G2677T/A) and exon 26 (C3435T) of MDR1 gene on the absorption of valacyclovir after a single oral administration in the Chinese Han ethnic population. Two hundred healthy Chinese subjects were genotyped for the SNPs of C1236T, G2677T/A and C3435T in the MDR1 gene using allele-specific polymerase chain reaction. Linkage disequilibrium (LD) was analysed. Twenty-four subjects derived from a large random sample (n = 200) received a single oral dose of 600 mg valacyclovir. Plasma concentrations of acyclovir were determined up to 14 h after administration to obtain a pharmacokinetic profile. LD existed between G2677T/A in exon 21 and C3435T in exon 26 (P < 0.001), between C1236T in exon 12 and C3435T (P < 0.001), but not between C1236T and G2677T/A (P > 0.05). C(max), AUC(0-1.5 h) and AUC(0-infinity) were used as indices of valacyclovir absorption. AUC(0-infinity) for the 2677TA genotype was 17.45 +/- 2.40 microg x h/ml, which was much higher compared with the 2677GG, GA and TT genotypes of 10.44 +/- 1.00, 11.84 +/- 2.83, 11.34 +/- 2.32 microg x h/ml, respectively (P < 0.05). Similarly, a statistically significant difference of AUC(0-infinity) was also observed for different linked genotypes at position 2677 vs. 3435, and 1236 vs. 3435 (P < 0.05). However, there was no significant difference in valacyclovir absorptive pharmacokinetics between carriers and noncarriers of different haplotypes (P > 0.05). Three SNPs of MDR1 gene did not influence the absorption of a single oral dose of 600 mg valacyclovir in healthy Chinese Han ethnic subjects.

Interaction between Valproic Acid and Acyclovir after Intravenous and Oral Administration in a Rabbit Model

This study was undertaken to investigate the effect of co-administration of valproic acid and acyclovir on the pharmacokinetic parameters of each other. Fifteen white New Zealand rabbits were divided into three groups: A, B and C. Group A received acyclovir only, group B received valproic acid only and group C received a combination of acyclovir and valproic acid. In a cross-over design, the intravenous route was studied first, followed by the oral route after a 2-week wash-out period. Blood samples were drawn over 10 hr and the pharmacokinetic parameters were derived from the concentrations. After intravenous administration, the area under the plasma concentration time curve and plasma concentrations of acyclovir in group C were higher than in group A, while the volume of distribution and plasma clearance of acyclovir in group C were only 12.8% and 10.36% of those of group A, respectively. A similar trend was observed after oral administration. However, the bioavailability (F) of acyclovir was 8.4% in group A versus 1.5% in group C. In addition, the concentrations and kinetic parameters of valproic acid between the two groups after oral and intravenous administration were not different. In conclusion, co-administration of single doses of acyclovir and valproic acid led to reduced oral bioavailability of acyclovir, but increased concentrations of acyclovir due to reduced volume of distribution and clearance. These observations call for a cautious approach to the concomitant use of the two drugs until human studies are done.

Clinical utility of oral valacyclovir compared with oral acyclovir for the prevention of herpes simplex virus mucositis following autologous bone marrow transplantation or stem cell rescue therapy

Oral acyclovir has been demonstrated to prevent reactivation of herpes simplex virus (HSV) infections when administered prophylactically to autologous bone marrow transplant (BMT) recipients or patients undergoing stem cell rescue therapy. Oral valacyclovir, which is converted in the body to acyclovir, has greater oral bioavailability than oral acyclovir and compared with oral acyclovir yields similar acyclovir plasma concentrations with less frequent (twice-daily) dosing. This study compared the efficacy of oral valacyclovir with that of oral acyclovir at preventing HSV mucositis in BMT recipients. A total of 60 HSV-1-positive patients scheduled for BMT or stem cell rescue therapy were treated prophylactically with valacyclovir 500 mg twice daily until resolution of neutropenia. Data from these patients were compared with those of a historical control group of 60 patients who had received acyclovir 600 mg every 6 h until resolution of neutropenia or acyclovir 125 mg/m(2) intravenously every 6 h. The results show that none of the patients developed oral or oropharyngeal HSV infection while receiving either treatment. Of the 60 patients receiving valacyclovir, 38 (63%) completed treatment without the need for intravenous acyclovir compared with 12 of 60 (20%) patients in the acyclovir group. Additionally, the total number of doses of drug administered to the valacyclovir group was significantly less than the number received by patients in the acyclovir group. No serious adverse events occurred in either group of patients. This study demonstrates that oral valacyclovir and acyclovir are comparably effective and safe in preventing reactivation of HSV infections in autologous BMT and stem cell recipients. The less frequent dosing schedule with valacyclovir compared with acyclovir offers a potential advantage for patients undergoing BMT who frequently suffer with severe mucositis and have difficulty taking oral medications.

Determination of acyclovir in plasma by solid-phase extraction and column liquid chromatography.

After oral administration, valacyclovir, the L-valyl ester of acyclovir, converts to the antiherpes virus drug, acyclovir. The bioavailability of acyclovir after valacyclovir administration is between 3- to 4.5-fold higher than that achieved after oral acyclovir administration. Therefore, despite the drug's short terminal half-life (3 hours), acyclovir plasma concentrations obtained after oral administration of the prodrug offer a more convenient dosage regimen in patients with herpes zoster than that required after acyclovir administration. Acyclovir is also used for viral infection prophylaxis in patients with hematologic disorders and in those who have undergone solid organ transplantation. We have described a simple and selective liquid chromatographic method for the determination of acyclovir in plasma using a new polymeric reversed-phase sorbent for solid-phase extraction. A mean acyclovir absolute recovery of 90% was found after elution of the drug from the cartridge with the mobile phase. This procedure allowed us to measure 62.5 ng/mL of acyclovir with an acceptable precision using a plasma volume of 250 microL, and no drug was found to interfere with the assay. This method is suitable for the therapeutic monitoring of acyclovir in patients who have been given a wide variety of coadministered drugs.

Acyclovir serum concentrations following peroral administration of magnetic depot tablets and the influence of extracorporal magnets to control gastrointestinal transit

In the present investigations peroral acyclovir depot tablets with internal magnets were developed. An extracorporal magnet was used to prolong the gastric residence times of the dosage forms and to influence the duration of absorption of acyclovir. The magnetic depot tablets contained 200 mg acyclovir. In a three-way cross-over in vivo study with five healthy male subjects, the plasma concentration-time profiles of acyclovir were determined. The acyclovir plasma concentrations following peroral administration of magnetic depot tablets in the presence and absence of an extracorporal magnet were determined. A commercially available immediate release preparation was used as a reference preparation. In the presence of an extracorporal magnet which was placed in the stomach region, the plasma concentrations of acyclovir were significantly higher after 7, 8, 10 and 12 h ( P<0.05, U-test, Wilcoxon, Mann–Whitney). The mean area under the plasma concentration-time-curve (AUC 0–24h), in the presence of the extracorporal magnet was 2802.7 ngh/ml. Without the extracorporal magnet a mean AUC 0–24h of 1598.8 ngh/ml was achieved. Computer simulations were carried out to show the influence of the gastric residence time of acyclovir depot preparations on the plasma concentration-time profiles of acyclovir.

Pharmacokinetics of oral valacyclovir and acyclovir in late pregnancy

Objective: The objective was to obtain preliminary pharmacokinetic data for acyclovir from gravid women receiving herpes simplex virus suppressive therapy with the acyclovir prodrug valacyclovir. Study Design: In a prospective, double-blind trial, 20 women with a history of recurrent genital herpes simplex virus infection and positive herpes simplex virus 2 serologic results were randomly assigned at 36 weeks’ gestation to receive oral valacyclovir (500 mg twice daily) or acyclovir (400 mg 3 times daily). Acyclovir pharmacokinetic profiles were obtained after the initial dose (36 weeks) and at steady state (38 weeks). Amniotic fluid samples were obtained during labor and simultaneous umbilical cord and maternal plasma samples were collected at delivery. Laboratory studies were performed to screen for laboratory evidence of toxicity in mothers and infants. Results: Peak acyclovir plasma concentrations (mean ± standard deviation) were higher in valacyclovir recipients than in acyclovir recipients after the initial dose (3.14 ± 0.7 μg/mL vs 0.74 ± 0.6 μg/mL, P < .0001) and at steady state (3.03 ± 1.0 μg/mL vs 0.94 ± 0.7 μg/mL, P < .001). The daily area under the curve values were higher in valacyclovir recipients than acyclovir recipients after the initial dose (17.8 ± 3.6 h · μg/mLvs 7.71 ± 2.5 h · μg/mL, P < .001) and at steady state (19.65 ± 6.4 h · μg/mL versus 11.0 ± 4.5 h · μg/mL, P = .009). There was no significant difference in drug elimination half-life or in time to peak concentration between valacyclovir and acyclovir recipients at either sampling interval. Acyclovir was concentrated in the amniotic fluid; however, there was no evidence of preferential fetal drug accumulation (mean maternal/umbilical vein plasma ratios at delivery were 1.7 for valacyclovir and 1.3 for acyclovir). Valacyclovir was well tolerated, and no significant laboratory or clinical evidence of toxicity was detected. Conclusion: In this phase I trial maternal valacyclovir therapy resulted in higher plasma acyclovir levels, with significantly higher peak concentrations and daily area under the curve values, than did acyclovir therapy. Additional trials are needed to further evaluate the safety and efficacy of suppressive valacyclovir therapy during late pregnancy. (Am J Obstet Gynecol 1998;179:846-51.)

Effect of Cyclosporine A on the Gastrointestinal Absorption of Acyclovir in Neonatal and Adult Rats

The effect of cyclosporine A (CyA) on the pharmacokinetics of acyclovir in neonatal and adult rats was studied. CyA at 25 and 50 mg/kg for 2-week-old and adult rats, respectively, given as a subcutaneous injection, reduced growth of the 2-week-old rats and inhibited growth of adult rats. The plasma concentration of acyclovir after intravenous administration (20 mg/kg) to neonatal CyA-treated rats increased and the total body clearance decreased compared with the neonatal controls. The bioavailabilities of acyclovir for neonatal control and CyA-treated rats after oral administration were significantly different at 15.6 and 22.0%, respectively, but those for the adult control and CyA-treated rats were the same at 15.6 and 14.0%, respectively. Experiments using the everted sac method showed that the amount of acyclovir transferred was higher in neonatal CyA-treated rats than the controls, but there was no difference in adult rats. A good relationship was observed between the bioavailabilities (in vivo) and cumulative transferred amounts (in vitro) in CyA-treated and control rats. Lactase activity in the brush border membrane of the intestine in the neonatal CyA-treated rats was significantly higher than in the controls. These results suggest that the gastrointestinal maturation of CyA-treated neonates is suppressed, resulting in increased bioavailability of acyclovir, while the gastrointestinal absorption of acyclovir does not differ between adult CyA-treated and control rats.