Acyclovir oral bioavailability

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. 

Tolle-Sander S, Lentz KA, Maeda DY, Coop A, Polli JW. Increased acyclovir oral bioavailability via a bile acid conjugate. Mol Pharm 2004 l(l) 40-48. 

The earliest cases of PORN were treated with intravenous acyclovir for a median of 2 weeks, followed by maintenance oral acyclovir. Most outcomes were dismal despite aggressive treatment, with only 18% of cases responding to therapy in a series. Maintenance oral acyclovir, with relatively low oral bioavailability was often unable to prevent recurrence of PORN. 

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. 

The oral bioavailability of acyclovir is poor and ranges from 10-30%. The drug is poorly protein bound but is widely distributed throughout body fluids and tissues, including the cerebrovascular fluid. It is primarily excreted unchanged in the urine (Wagstaff et al., 1994). 

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... 

The antiherpetic agent acyclovir suffers from poor oral bioavailability only 10-20% of an oral dose is absorbed in humans. This can be essentially ascribed to low water solubility due to strong interaction forces in the crystal lattice. The corresponding deoxo derivative (6-deoxyacyclovir) was shown by Krenitsky to be 18 times more water soluble and to be rapidly oxidized in vivo by xanthine oxidase... 

Ghosh, P.K., Majithiya, R.J., Umrethia, M.L. andMurthy, R.S.R. (2006) Design and development of microemulsion drug delivery system of acyclovir for improvement of oral bioavailability. AAPS Pharmscitech, 7, 77. 

Research to improve the oral bioavailability of acyclovir has resulted in the development of its L-valyl ester, valaci-clovir. Oral valaciclovir is rapidly and extensively converted to acyclovir, substantially increasing acyclovir bioavailability, and thus it has the potential for improved efficacy and more convenient dosing than oral acyclovir (see also Figure 16). 

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). 

Soul-Lawton, J., Seaber, E., On, N., Wootton, R., Roian, P., Posner, J., Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans, Antimicrob. Agents Chemother. 1995, 39, 2759— 2764. 

Steingrimsdottir, H., Gruber, A., Palm, C., Grimfors, G., Kalin, M., and Eksborg, S., Bioavailability of acyclovir after oral administration of acyclovir and its prodrug valaciclovir to patients with leukopenia after chemotherapy, Antimicrob. Agents Chemother., 44, 207, 2000. 

The bioavailability of oral acyclovir is low (15-20%) and is unaffected by food. An intravenous formulation is available. Topical formulations produce high concentrations in herpetic lesions, but systemic concentrations are undetectable by this route. 

The bioavailability of oral acyclovir is 15-20% and is unaffected by food. Peak serum concentrations of approximately 1 uglmL after a 200 mg oral dose and 1.5-2 ugJmL after an 800 mg dose are reached 1.5-2 hours after dosing. Peak serum concentrations are 10 ugJmL and 20 m g/mL after intravenous infusions (over 1 hour) of 5 mg/kg and 10 mg/kg, respectively. Topical formulations produce local concentrations that may exceed 10 g/mL in herpetic lesions, but systemic concentrations are undetectable. 

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