Theoretical Considerations on Two Equations for Estimating the Extent of Absorption After Oral Administration of Drugs

Purpose. The amount of drug absorbed into portal blood after oral dosing (D_p.o,g) has been estimated using Ficks principle (Q-method), i.e., D_p.o,g = Q_h · (AUC_p.o,g – AUC_p.o,c), where Q_h is the portal blood flow rate, and AUC_p.o,g and AUC_p.o,c are the areas under the concentration-time curves of portal vein and systemic blood after oral dosing, respectively. However, this method may underestimate D_p.o,g, when the drug is subject to systemic intestinal elimination. An alternate equation (CL-method; D_p.o,g = CL_S · AUC_p.o,g) is described using a simple pharmacokinetic model, to estimate D_p.o,g in the presence of systemic intestinal elimination, where CL_S is systemic clearance. Methods. The model is composed of central, intestine and liver compartments, assuming that drug is eliminated by intestinal and/or hepatic pathways only. A comparison of both methods for estimating D_p.o,g was made using computer-simulation or experimental data of phenacetin from the literature. Results. The simulation study demonstrated that the Q-method underestimated D_p.o,g in the presence of significant intrinsic intestinal clearance, compared to the CL-method,. The similar results were observed using the experimental data of phenacetin. Conclusions. The CL-method can provide a better estimate of D_p.o,g, while the Q-method may underestimate D_p.o,g, when there is significant systemic intestinal elimination of drugs after oral administration. In addition, useful information for understanding the relationship between the extent of absorption and the first-pass effect by intestine and/or liver after oral dosing of drugs can be obtained from the present approach.     

Membrane Transport in Hepatic Clearance of Drugs I: Extended Hepatic Clearance Models Incorporating Concentration-Dependent Transport and Elimination Processes

Purpose. The objective of the present study was to develop hepatic clearance models which incorporate a unidirectional carrier-mediated uptake and bidirectional diffusional transport processes for drug transport in the sinusoidal membrane of hepatocytes as well as nonlinear intrinsic elimination. Methods. Two models were derived which view the liver as two separate compartments, i.e., sinusoid and hepatocyte. Model I assumes the instantaneous complete mixing of drugs within each compartment (similar to that of the 'well-stirred' model), while model II assumes that the drug concentrations in both compartments decrease progressively in the direction of the hepatic blood flow path (similar to that of the 'parallel-tube' model). Computer simulations were performed using a range of steady-state infusion rates for a substrate, while varying theV _max (capacity) and K _m (Michaelis-Menten constant) for the carrier-mediated uptake process, the diffusional clearance, the V _max and K _m for the intrinsic elimination process, blood flow and protein binding. Results. Simulations in which V _max and K _m for the sinusoidal membrane transporter and the diffusional clearance were varied, demonstrated that these membrane transport processes could affect the clearance of drugs to a significant extent in both models. The estimates for clearance of substrates with the same pharmacokinetic parameters are always lower in model I than in model II, although the quantitative differences in parameter estimates between models varied, depending on the steady state infusion rates. Conclusions. These more general hepatic clearance models will be most useful for describing the hepatic clearance of hydrophilic compounds, such as organic anions or cations, which exhibit facilitated uptake and limited membrane diffusion in hepatocytes.     

Lack of pharmacokinetic interaction for ISIS 113715, a 2'-0-methoxyethyl modified antisense oligonucleotide targeting protein tyrosine phosphatase 1B messenger RNA, with oral antidiabetic compounds metformin, glipizide or rosiglitazone

BACKGROUND: ISIS 113715 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that is complementary to the protein tyrosine phosphatase 1B (PTP-1B) messenger RNA and subsequently reduces translation of the PTP-1B protein, a negative regulator of insulin receptor. ISIS 113715 is currently being studied in early phase II clinical studies to determine its ability to improve or restore insulin receptor sensitivity in patients with type 2 diabetes mellitus. Future work will investigate the combination of ISIS 113715 with antidiabetic compounds. METHODS: In vitro ultrafiltration human plasma protein binding displacement studies and a phase I clinical study were used to characterise the potential for pharmacokinetic interaction of ISIS 113715 and three marketed oral antidiabetic agents. ISIS 113715 was co-incubated with glipizide and rosiglitazone in whole human plasma and tested for increased free drug concentrations. In a phase I clinical study, 23 healthy volunteers received a single oral dose of an antidiabetic compound (either metformin, glipizide or rosiglitazone) both alone and together with subcutaneous ISIS 113715 200 mg in a sequential crossover design. A comparative pharmacokinetic analysis was performed to determine if there were any effects that resulted from coadministration of ISIS 113715 with these antidiabetic compounds. RESULTS: In vitro human plasma protein binding displacement studies showed only minor effects on rosiglitazone and no effect on glipizide when co-incubated with ISIS 113715. The results of the phase I clinical study further indicate that there were no measurable changes in glipizide (5 mg), metformin (500 mg) or rosiglitazone (2 mg) exposure parameters, maximum plasma concentration and the area under the concentration-time curve, or pharmacokinetic parameter, elimination half-life when coadministered with ISIS 113715. Furthermore, there was no effect of ISIS 113715, administered in combination with metformin, on the urinary excretion of metformin. Conversely, there were no observed alterations in ISIS 113715 pharmacokinetics when administered in combination with any of the oral antidiabetic compounds. CONCLUSION: These data provide evidence that ISIS 113715 exhibits no clinically relevant pharmacokinetic interactions on the disposition and clearance of the oral antidiabetic drugs. The results of these studies support further study of ISIS 113715 in combination with antidiabetic compounds.     

Hepatic Membrane Transport of Organic Cations Using Isolated Rat Hepatocyte Membrane Vesicles: Structure–Transport Relationships

Pharmaceutical Research -     

Membrane Transport in Hepatic Clearance of Drugs II: Zonal Distribution Patterns of Concentration-Dependent Transport and Elimination Processes

Purpose. The objective of the present simulation study was to investigate the effects of hepatic zonal heterogeneity of membrane transporter proteins and intrinsic elimination activities on hepatic clearance (CL) and drug concentration gradient profiles in the sinusoidal blood and hepatocytes. Methods. The model used in the simulations assumes an apparent unidirectional carrier-mediated transport and a bidirectional diffusion of substrates in the hepatic sinusoidal membrane as well as a nonlinear intrinsic elimination. Three different distribution patterns of the transporter and the metabolizing enzyme along the sinusoidal flow path were used for the simulations. The effects of changes in the Michaelis-Menten parameters for those nonlinear processes, and in the unbound fractions of the drug in blood and tissue components were investigated. Results. Significant differences in CL occurred when the distribution patterns of the transporter and/or the metabolizing enzyme activities were altered under nonlinear conditions. The highest CL values were observed when the transporter and the metabolizing enzyme had similar distribution patterns within the liver acinus, while opposite distribution patterns produced the lowest CL values. Tissue concentration profiles were significantly affected by the distribution patterns of the transporter, but the changes in blood concentration profiles were relatively small. Altering protein binding in blood produced significant changes in CL, and blood and tissue concentration gradients, while altering protein binding in tissue affected only drug accumulation patterns within hepatocytes, regardless of the distribution patterns of the transporter or the metabolizing enzyme. Conclusions. The present simulations demonstrate that hepatic zonal heterogeneities in the transporter and the metabolizing enzyme activities can significantly influence hepatic clearance and/or drug concentration gradient profiles in the sinusoidal blood and hepatocytes.     

Substance P enhances EPC mobilization for accelerated wound healing

Wound healing is essential for the survival and tissue homeostasis of unicellular and multicellular organisms. The current study demonstrated that the neuropeptide substance P (SP) accelerated the wound healing process, particularly in the skin. Subcutaneous treatment of SP accelerated wound closing, increased the population of α‐smooth muscle actin positive myofibroblasts, and increased extracellular matrix deposition at the wound site. Moreover, SP treatment enhances angiogenesis without a local increase in the expression levels of vascular endothelial growth factor and stromal cell‐derived factor‐1. Importantly, SP treatment increased both the population of circulating endothelial progenitor cells in the peripheral blood and in CD31 positive cells in Matrigel plugs. The tube forming potential of endothelial cells was also enhanced by SP treatment. The results suggested that the subcutaneous injection of SP accelerated the wound healing in the skin via better reconstitution of blood vessels, which possibly followed an increase in the systemic mobilization of endothelial progenitor cells and a more effective assembly of endothelial cells into tubes.     

Effects of diffusional barriers on the extent of presystemic and systemic intestinal elimination of drugs

In the present study, a pharmacokinetic model to address the effects of the diffusional barrier between splanchnic bed and enterocytes on the extent of presystemic and systemic intestinal elimination of drugs was developed. The model is composed of five compartmentsi.e., gut lumen, enterocyte, splanchnic bed, liver and central compartments. The equations for various pharmacokinetic parameters important for estimating the quantitative differences between prresystemic and systemic intestinal and hepatic elimination of drugs were derived. A simulation study demonstrated that the diffusional barrier present between splanchnic blood and enterocytes can have significant effects on oral bioavailability and systemic clearance of drugs. In conclusion, the model can be useful for a better understanding of the effects of diffusional barrier on the extent of administration-route dependent intestinal and hepatic elimination of drugs, especially those with high hydrophilicity and/or charge(s) under physiological conditions.