Pathway Tenofovir/Adefovir Pathway, Pharmacokinetics

Representation of candidate genes involved in renal elimination of tenofovir and adefovir and their mechanism of action in an infected kidney cell
Tenofovir/Adefovir Pathway, Pharmacokinetics
tenofovir adefovir tenofovir adefovir tenofovir adefovir tenofovir adefovir diplvoxil tenofovir adefovir slc22a6 slc22a8 ak2 ak4 nme1 nme2 abcc4 abcc4 abcc10
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Description

Tenofovir (trade name Viread) and adefovir (trand name Hepsera) are acyclic nucleotide analogs of adenosine monophosphate. Tenofovir exhibits antiviral activity against HIV reverse transcriptase (HIV RT) whereas adefovir exhibits antiviral activity against human hepatitis B virus reverse transcriptase (HBV RT). Both drugs have been associated with renal toxicity. (Viread and Hepsera package insert, http://www.gilead.com/pdf/viread_pi.pdf; http://www.gilead.ca/pdf/hepsera_pi.pdf.)

Pharmacokinetics

Tenofovir/adefovir dipivoxil require initial diester hydrolysis for conversion to tenofovir/adefovir. Each drug is phosphorylated twice to the diphosphate form, which is the active antiviral form. The enzymes catalyzing the phosphorylation steps are adenylate kinases (AK2 and AK4) and nucleotide diphosphate kinases (NME1 and NME2). Tenofovir /adenovir exhibit little (<10%) protein binding to human plasma or human serum proteins. They are not metabolized by any of the cytochrome P450s. The major route of elimination is through the kidneys via glomerular filtration and tubular secretion. Clearance in the proximal tubule of the renal nephron is controlled mostly by membrane transport proteins. Organic anion transporter 1 (OAT1) (SLC22A6) and organic anion transporter 3 (OAT3) (SLC22A8) on the basolateral membrane of the human proximal tubule kidney cell, and multidrug resistance protein 4 (MRP4) (ABCC4) on the apical side are the major transporters involved in tenofovir/adefovir clearance [Articles:11563082, 17372702, 17503669]. SLC22A6 and SLC22A8 act in the uptake of tenofovir/adefovir into the renal proximal tubule cell while ABCC4 controls the active efflux of the drug across the apical membrane. [Articles:11563082, 17503669, 17110501]. The multidrug resistance protein 2 (MRP2) encoding the ABCC2 gene has also been implicated in the efflux process [Articles:17597712, 17083032, 19842939]. Genetic variation in SLC22A6, SLC22A8 and ABCC4 may therefore influence exposure of the kidney to tenofovir/adefovir and thus, play a major role in tenofovir/adefovir associated renal toxicity. [Articles:15914676, 15864112, 17110501] Drugs that interact with SLC22A6, SLC22A8 and ABCC4 may play a role in tenofovir/adefovir associated toxicity.

Pharmacodynamics

In viral infected cells, tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with its natural nucleotide counterpart deoxyadenosine 5'-triphosphate for incorporation into newly synthesized viral DNA. Once incorporated, it leads to termination of DNA elongation and stops further DNA synthesis.

Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with its nucleotide counterpart deoxyadenosine triphosphate for incorporation into viral DNA. Once incorporated, it leads to termination of viral DNA elongation.

Pharmacogenetics

Tenofovir has been shown to be relatively safe (PMID: 17545703) but several studies have now shown that it may induce renal proximal tubulopathy (rPT) [Article:17083032] and cause kidney tubular dysfunction [Article:21628669]. The mechanism underlying these adverse events is probably related with renal clearance of TFV. It has been reported that higher TFV plasma levels may lead directly to its greater accumulation in the renal tubular cells likely resulting in kidney toxicity (PMID: 20299966). Once tenofovir enters tubular cells, it is actively secreted by transporters on the luminal membrane. For the majority of antiviral drugs, this efflux at the luminal membrane is a rate limiting step which may result in intracellular accumulation. Also, the expression of the transporter may impact the extent of tubular damage. A high degree of variability in disease occurrence and severity has been shown [Article:19842939] and several genetic variants of transporters have been linked to these phenotypes [Articles:17083032, 19400747]. In the ABCC2 gene, homozygosity for the C allele at position -24 has been associated with tubular renal damage[Article:19400747]. This polymorphism may be used to identify patients at greater risk for developing tenofovir-associated tubulopathy, and these patients can receive close monitoring of renal function during treatment with TFV. A study by Hassane Izzedine et al, based on haplotype frequency showed that the ABCC2 haplotype (-24 C/T, 1249 G/A, 3563 T/A, and 3972 C/T) is significantly associated with the development of TFV-induced renal proximal tubulopathy [Article:17083032]. The ABCC4 3463G allele has also been associated with higher intracellular concentrations of TFV [Article:18398970]. Recently, a study by Pushpakom et al, has shown that TFV is a substrate of ABCC10 and two SNPs, rs9349256 and rs2125739 and the GGC haplotype are associated with increased risk of kidney tubular dsyfunction for patients being treated with TFV [Article:21628669].

Authors: Debbie Lin, Li Gong, Kathleen M. Giacomini, Milcah Dhoro.
Citation:
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
History:
Therapeutic Categories:
  • Anti-infective agents