Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK
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Abstract |
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Keywords: P-glycoprotein , pharmacokinetics , HIV , efflux , influx
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Introduction |
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There is increasing interest in the use of therapeutic drug monitoring (TDM), to aid optimization of antiretroviral therapy; this has the potential to both reduce toxicity and ensure adequate viral suppression. However, the major target of PIs is within cells infected with HIV and clinical outcome ultimately must be related to intracellular drug concentrations. Therefore, it is important that factors influencing viral replication and evolution within lymphocytes be fully understood. In HIV-1-infected peripheral blood mononuclear cells (PBMCs) and cell lines, the antiviral activity of PIs is highly correlated with the intracellular concentration of drug,4,5 which has formed the rationale for in vivo studies on intracellular PIs. Intracellular pharmacokinetics provides information regarding drugs in a compartment where HIV replication occurs and combined with plasma data may give insights into understanding therapeutic failure in relation to cellular resistance.
In vitro PIs accumulate in the following order: nelfinavir > saquinavir > ritonavir > indinavir in an adenocarcinoma cell line,6 nelfinavir > saquinavir > ritonavir = lopinavir > indinavir in buffy coat cell subsets ex vivo7 and saquinavir > amprenavir > indinavir in subcellular HeLa cell fractions.8 Furthermore, there is a hierarchy of intracellular accumulation in HIV-1 infected patients in vivo, saquinavir > ritonavir > indinavir9 and nelfinavir > amprenavir > indinavir.10 The main areas of pharmacology that influence intracellular drug concentrations are oral bioavailability, plasma protein binding (altering the free fraction of drug), physiochemical properties (such as lipophilicity, degree of ionization), cellular protein binding and cellular influx/efflux active transport (Table 1).
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Bioavailability |
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Plasma protein binding |
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Physiochemical properties |
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Passive diffusion through a membrane is determined by the size of the molecule, unbound drug concentrations, degree of ionization and lipophilicity. The partition coefficient of a compound between water and a lipophilic solvent such as n-octanol is one model utilized to describe the potential accumulation of a compound. Nelfinavir is the most lipophilic PI having the highest partition coefficient, and may therefore passively diffuse into the intracellular compartment to a greater extent compared with other PIs. Log P values for the PIs have been reported in the following order: nelfinavir > saquinavir > amprenavir = lopinavir > ritonavir > indinavir (Table 1), providing an indication of the lipophilicity of the compounds.7 Accumulation of PIs in lymphocytes and subsets reflects the lipophilicity rank order, suggesting that passive diffusion is important in the bioaccumulation of each PI.
Ion trapping
Membranes are impermeable to ionized forms of drugs and so the degree of ionization of a molecule affects the concentration that is available for passive diffusion across biological membranes. Since the dissociation constant (pKa) is equal to the pH at which a compound is 50% ionized, then weak bases will mainly be un-ionized in a basic environment and if lipophilic may be absorbed. Therefore nelfinavir, pKa 6.0/11.1, saquinavir pKa 1.1/7.1 and indinavir pKa 6.212 (Table 1), which are weak bases, are more likely to cross lipid membranes of cells or organelles when the pH of the environment is greater than the pKa of PIs. Thus there is the potential for sequestration of basic compounds (pKa > 8) in acidic compartments and the pH gradient between plasma and lymphocytes will influence ion trapping. The pH gradient between plasma and lymphocytes is subject to change depending on the membrane potential.
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Protease inhibitor intracellular accumulation |
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The accumulation of PIs in vivo mirrors the hierarchy that has been observed from in vitro studies nelfinavir > saquinavir > amprenavir > M8 > lopinavir ritonavir > indinavir (Table 2) and accumulation of PIs appears to reflect the rank order of lipophilicity. However, some in vitro and ex vivo studies suggest that passive diffusion is not the only explanation for accumulation6,7 and other factors such as active transport may be important.
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Another issue regarding intracellular drug concentrations is whether extrapolation from simultaneous plasma concentrations can be carried out and if plasma TDM has the potential to be a surrogate marker for cell-associated concentrations. Conflicting data surrounding this matter have been reported with studies suggesting extrapolation of saquinavir, indinavir and nelfinavir may be possible15,1820 whilst for other PIs lopinavir,15 ritonavir and M816,21 studies suggest extrapolation is difficult. Generally interpretation of intracellular PI concentrations from corresponding plasma levels is complicated with many interrelated factors involved and each individual PI may behave differently. Further clinical trials using large patient numbers are required to address this issue. A recent study has shown that baseline lopinavir mutations giving rise to virological failure were associated with both low intracellular and plasma concentrations. The authors suggested that monitoring the efficacy of lopinavir and ritonavir should include measurement of baseline mutations, intracellular and plasma concentrations.22
Generally, intracellular drug concentrations obtained from different laboratories have generated consistent data, however, some differences in the data are present. In order to improve the performance of assays, and expand intracellular pharmacokinetic data, procedures should be standardized so as to produce accurate and reproducible assays in human peripheral blood mononuclear cells.
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Drug transporter proteins |
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P-gp plays a major role in cancer therapy resistance, preventing sufficient intracellular accumulation of several anticancer agents due to expression in various types of cancer. Therefore it is thought that resistance can be overcome by inhibition of P-gp. Many first- and second-generation inhibitors have displayed poor efficacy. However, third-generation inhibitors such as XR9576 have shown higher potency, selectivity and demonstrated inhibition of P-gp in a solid tumour model.55 Relatively few studies have compared surface expression levels of transporters with the intracellular accumulation of PIs in vivo. Some in vivo studies have shown P-gp expression on the surface of lymphocytes to be related to accumulation of ritonavir56 and lopinavir and ritonavir21 whilst others have shown no relationship with nelfinavir or M816 or once daily saquinavir and ritonavir18 accumulation. Another study showed an inverse relationship between overexpression of the P-gp MDR1 gene and lower intracellular concentration of PI.10 Therefore there appears to be a disconnect between P-gp transporter data in vitro and in vivo and one must be careful when interpreting in vitro data. Similar disconnects between in vitro and clinical data have been observed previously when in vitro studies showed nelfinavir to up-regulate P-gp expression in vitro at 10 µM5760 but patients on PI- and non-PI-based regimens exhibited no difference in expression of P-gp.60,61
Reports have indicated that patients with MRP1 expression lower than the median displayed significantly higher saquinavir and ritonavir accumulation,56 whereas lopinavir accumulation was not related to expression of MRP1.21 The PIs are substrates for MRP2, another transporter that may influence intracellular drug levels.62 However, this transporter is not expressed on lymphocytes63 and so will not affect lymphocyte accumulation of PIs directly. However, BCRP may play an important role in the transport of some antiretrovirals, since it appears to be expressed on lymphocytes45 to a similar extent as P-gp, and confers cellular resistance to zidovudine, a nucleoside reverse transcriptase inhibitor.45 Although few studies have investigated BCRP transport of substrates, a recent article suggests that the PIs are not substrates for BCRP.64 Relationships between PI accumulation and BCRP expression remain to be determined in vitro and in vivo.
Polymorphisms in the genes encoding transporter proteins, receptors, and drug-metabolizing enzymes have been associated with inter-individual variation. Genetic variations in the MDR1 gene have been extensively studied and generated inconsistent and variable data.65 Single nucleotide polymorphisms (SNPs) have been identified in the MDR1 gene and a relationship has been observed between a C3435T SNP in exon 26 and P-gp expression in the intestine66 and on PBMCs.67 Some studies have demonstrated individuals with the TT genotype to have high plasma digoxin levels68 whereas other studies have shown TT individuals to have low plasma fexofenadine69 or efavirenz and nelfinavir concentrations.67 One recent study demonstrated an association between individuals with the homozygous variant genotype (TT) and higher plasma and intracellular nelfinavir exposure.70 However, the SNP is in a non-coding wobble position. This has generated many questions as to how this SNP actually correlates with reduced expression and function of P-gp. Hypotheses69,71 propose that the polymorphism in exon 26 is linked to other SNPs such as G2677T located in exon 21, since haplotype combinations of SNPs are likely to be superior to single SNPs. It is possible that C3435T is linked to a SNP that affects MDR1 gene expression in a regulatory region such as a promoter or enhancer region or is possibly linked to another polymorphic gene such as steroid xenobiotic receptor (SXR) or CYP P450 enzymes. Clearly, to understand polymorphic studies, assays for measuring protein and mRNA need to be standardized.
The lack of consistency in reported data indicate that combinations of multiple efflux transporters are more likely to be responsible. In addition, since PIs have different affinities for different transporters such as P-gp,51 it may be that a particular PI is influenced by one transporter more than another. Moreover, many different methods are available to measure expression, function or gene expression of transporters. Generally, extrapolation of in vitro to clinical data is difficult when many interrelating factors are involved in vivo.
Organic anion and cation transporters are two other major classes of transport proteins, however few data exist about their expression on lymphocytes. Organic anion transporters (OAT) have been cloned and belong to one of the following gene families: OAT, OATP or OAT-K72 whilst organic cation transporters (OCT) belong to either the OCT or OCTN family73 (Table 4). Few studies have investigated the role of organic anion and cation transport proteins in the transport of antiretrovirals. However, the PIs saquinavir, ritonavir, indinavir and nelfinavir have been shown to inhibit OCT1 in vitro, which has the potential to cause drug interactions.74 A more recent study identified that OATP-A transports saquinavir in vitro75 and the clinical relevance of this finding remains to be determined. SNPs have also been identified in OATP-C, causing a functional alteration in transport, since several variants exhibited reduced uptake of OATP-C substrates.76 Three SNPs have been identified in the human carnitine transporter gene (OCTN-2) leading to subsequent carnitine deficiency.77 In addition, variants of OAT1 have been identified as a result of alternative splicing with some splice variants (OAT1-3 and OAT1-4) reported to be potentially non-functional.73
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Summary |
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Acknowledgements |
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Footnotes |
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References |
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