Valacyclovir oral bioavailability

Phan DD, Chin-Hong P, Lin ET, Anderle P, Sadee W, Guglielmo BJ. Intta- and interindividual variabilities of valacyclovir oral bioavailability and effect of coadministration of an hPEPTl inhibitor. Antimicrob Agents Chemother (2003) 47, 2351-3. 

Some drugs with low intrinsic permeability achieve acceptable oral bioavailability because they are substrates for uptake transporters, which normally function in nutrient uptake. The most prominent example is the peptide transporter, PepTl, which is active toward peptidomimetic antibiotics such as cephalexin, the antiviral agent valacyclovir [24] and other drugs. PepTl is natively expressed in Caco-2 cells, and adenovirus transduction has been used to increase PepTl expression levels [25]. However, the expression of PepTl was not polarized in this system and this expressed system appears to be of limited value as an improved screening model. PepTl has also been expressed in Chinese hamster ovary cells and a variety of other mammalian systems [26, 27]. 

Valacyclovir is the L-valyl ester of acyclovir (Figure 49-2). It is rapidly converted to acyclovir after oral administration via first-pass enzymatic hydrolysis in the liver and intestine, resulting in serum levels that are three to five times greater than those achieved with oral acyclovir and approximate those achieved with intravenous acyclovir. Oral bioavailability is 54-70%, and cerebrospinal fluid levels are about 50% of those in serum. Elimination half-life is 2.5-3.3 hours. 

After oral administration and absorption, valacyclovir is converted to acyclovir, which is the active antiviral component of valacyclovir. The antiviral activity and mechanism of action of valacyclovir is identical to that of acyclovir (Perry and Faulds, 1996). The oral bioavailability of valacyclovir is significantly greater than that of acyclovir. Oral administration of valacyclovir results in plasma acyclovir concentrations comparable to those observed with intravenous acyclovir. 

Valacyclovir is an ester prodrug of acyclovir. It provides significantly better oral bioavailability compared to acyclovir. This advantage results in substantially higher serum acyclovir concentrations than is possible with oral acyclovir. In addition, fewer daily doses are required with valacyclovir (Curran and Noble, 2001). 

Valacyclovir is the L-valyl ester of acyclovir, with oral bioavailability three to five times that of oral acyclovir. Following ingestion, it is rapidly converted by intestinal and hepatic hydrolases to acyclovir. Valacyclovir has gastrointestinal and neurological side effects similar to those seen with acyclovir. To date, significant nephrotoxicity and crystalluria as seen with acyclovir has only rarely been reported with... 

Oral bioavailability of acyclovir (-10-30%) decreases with increasing dose. Valacyclovir is converted rapidly and virtually completely to acyclovir after oral administration. This conversion reflects first-pass intestinal and hepatic metabolism by enzymatic hydrolysis. Unlike acyclovir, valacyclovir is a substrate for intestinal and renal peptide transporters. The oral bioavailability of acyclovir increases to -70% following valacyclovir administration. Peak acyclovir concentrations occur -2 hours after dosing. Peak plasma concentrations of valacyclovir are only 4% of acyclovir levels. Less than 1% of an administered dose of valacyclovir is recovered in the urine, and most is eliminated as acyclovir. 

Uptake transporter prodrug substrates have been used to improve drug absorption through GI tract. The most successful example is an antiviral prodrug valacyclovir, which shows oral bioavailability three to live times greater than its parent drug acyclovir (Weller et al., 1993). The increased oral bioavailability is attributed to PEPTl-mediated absorption, which was demonstrated by in situ rat perfusion model, Caco-2 cells, and PEPTl-transfected CHO cells (Balimane et al., 1998). 

Valacyclovir, a prodmg of acyclovir, is available only in oral formulation.Valacyclovir is hydrolyzed by esterases in the gastrointestinal tract and liver, converting more than 95% to acyclovir, to provide significantly greater bioavailability than oral acyclovir. 

Systemic antiviral therapy promotes resolution of HZO skin lesions and reduces the incidence and severity of dendriform keratopathy, anterior uveitis, and stromal keratitis by decreasing the rate of virus replication. All patients with acute HZO should receive antiviral therapy with the goal of minimizing ocular complications. Acyclovir, valacyclovir, and femciclovir are FDA approved for management of herpes zoster. Acyclovir usually is administered orally in dosages of 800 mg five times per day far 7 days. Valacyclovir has better bioavailability when taken orally and can be used with a recommended dosage of 1 g three times a day for 7 days. Famciclovir, which has bioavailability similar to valacyclovir, has an increased half-life and also has the advantage of less frequent administration than acyclovir 500 mg three times a day for 7 days. 

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