Rapid determination of acyclovir, its main metabolite 9‐carboxymethoxymethylguanine, ganciclovir, and penciclovir in human serum using LC–MS/MS

Abstract

A novel MS-based analytical method for simultaneous analysis of the antiviral drugs acyclovir, its metabolite 9-carboxymethoxymethylguanine, ganciclovir, and penciclovir in human serum is described. These antiviral drugs are active against herpes virus infections. Acyclovir and penciclovir are regarded as safe and effective medicines with mild side effects such as headache and gastrointestinal discomfort, and ganciclovir is regarded as more toxic and is known to cause, for example, bone marrow suppression. Acyclovir's main metabolite 9-carboxymethoxymethylguanine is a presumptive neurotoxin and should be monitored in patients with impaired renal function or in cases with neurotoxic symptoms. A sample was prepared using protein precipitation with 1% formic acid in methanol containing isotopically labeled internal standard. Chromatographic separation on a biphenyl column and mass spectrometric detection were performed in multiple reaction monitoring (MRM) mode on a Xevo TQ-S micro with ESI in positive ion mode, within 3 min. Inter-day assay accuracies for the quality controls varied between 95 and 104% and intra-day assay between 93 and 105%. Inter-day and intra-day assay imprecision for the quality controls ranged between 1.4 and 4.2% and 1.7 and 6.5% respectively. The lower limit of quantification for all four substances was 0.156 μmol/L. It is an accurate and reproducible method for therapeutic drug monitoring.

Development and Validation of an HPLC-UV Method for the Quantification of Acyclovir and Ganciclovir in the Plasma of Pediatric Immunocompromised Patients

“…The introduction of bromouracil as an IS, and therefore the simultaneous quantification of both antivirals, could allow the use of the same calibrators and quality controls, allowing us to reduce the costs and the timing of the analysis. Techniques different from HPLC-UV are employed to obtain this purpose [ 15 , 16 , 17 , 18 ]; instead, to the authors’ knowledge, only a few papers have described HPLC-UV methods able to quantify both of these antivirals, as the chromatographic separation of these antivirals is hard to obtain due to their similar chemical structure [ 19 , 20 , 21 ]. Among the limitations of our study, there is the impossibility of quantifying 9-carboxymethoxymethylguanine, the main metabolite of acyclovir responsible for side effects encountered after antiviral treatment, as found in another study conducted previously [ 18 ].…”

Method Development, Stability, and Pharmacokinetic Studies of Acyclovir-Loaded Topical Formulation in Spiked Rat Plasma

“…Furthermore, LLOD from earlier published reports were 1.06 µg/mL and 156 ng/mL [22,23]. The novelty and uniqueness of the current study employs an integrated method of experimental designs and simulations to determine the appropriate chromatographic method for the drug analysis in biological samples.…”

Folate-Targeted Nanocarriers Co-Deliver Ganciclovir and miR-34a-5p for Combined Anti-KSHV Therapy

“…Ganciclovir (GCV), also named 9-(1,3-dihydroxy-2-propoxymethyl) guanine, is a white crystalline powder that is a cyclic analog of endogenous nucleoside guanine and a small-molecule antiviral drug that inhibits viral genome replication by inhibiting the DNA polymerase protein of KSHV [ 8 , 9 , 10 ]. However, the transmembrane capacity of GCV is poor, and long-term intravenous administration is required to achieve the required concentration for treatment, which leads to various types of thrombocytopenia and persistent myelosuppression [ 11 ]. miR-34a-5p is a small molecule–nucleic acid belonging to the miR-34 family and has been proven to play an important role in the treatment of KSHV [ 12 ].…”