Drug distribution transporters

As in all standard two-compartment models, the rate of drug distribution transport between the two compartments is taken to follow first-order or linear kinetics. 

The rate of drug distribution transport between the central compartment (containing the systemic circulation) and any tissue compartment is taken to follow first-order or linear kinetics. This means that the rate of drug transport from compartment 1 to any other compartment is proportional to the amount of drug in compartment 1. Similarly, the rate of drug transport... 

In order to design such an efficient and effective device, one must understand the mechanisms by which drug is transported in the ocular interior. One issue debated in the literature for some time has been the relative importance of transport by passive diffusion versus that facilitated by the flow of fluid in the vitreous (see, e.g., Ref. 226). To predict the geometric distribution even at steady state of drug released from an implant or an intravitreal injection, one must appreciate which of these mechanisms is at work or, as appropriate, their relative balance. 

The thermodynamic solubility of a drug is the concentration of the compound that is dissolved in aqueous solution in equilibrium with the undissolved amount, when measured at 25°C after an appropriate time period. Aqueous solubility has long been recognized as a key molecular property in pharmaceutical science. Drug delivery, transport and distribution phenomena depend on solubility thus, it is of considerable value to possess information of the solubility value of a drug candidate, to be able to predict the solubility for unknown compounds and, finally, to be able to modify the structure of a compound in order to modulate its solubility value in an appropriate manner. 

There is evidence for the presence of other human OATPs including OATP-D [30], OATP-F (NM 017435] [39] and OATPRP4 (NM 030958). Further studies are required to determine the impact of these transporters on the drug distribution and elimination. 

Ganapathy V, Prasad PD, Ganapathy ME, Leibach FH. Placental transporters relevant to drug distribution across the maternal-fetal interface. J Pharmacol Exp Ther 2000 294(2) 413-420. 

K., Steiner, I Baumgartner, C. and Muller, M. (2005) Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous system drug distribution in humans. Clinical Pharmacology and Therapeutics, 78, 182-190. 

Figure 13.1. Compartmental model based on clearance and volume (Section 13.2.4.1). The drug is administered at a rate Ri into the central compartment, which is characterized by a volume of distribution K. The drug is transported to and from the peripheral compartment with inter-compartmental clearance CL12 and CL21, respectively (usually it is assumed that there is no net transport between the two compartments if the concentrations in both compartments are equal in this case CL21 = CLi2)- The peripheral compartment is characterized by a volume of distribution 1 2-Elimination may take place from both compartments and is characterized by clearance CL o and CL20, respectively.

Figure 13.2. Compartmental model based on rate constants (Section 13.2.4.1). The drug is administered at a rate into the central compartment, which is characterized by a volume of distribution V. The drug is transported to and from the peripheral compartment with rate constants and feii, respectively.

Although the impact of transporters on absorption appears to be moderate there is increasing evidence showing that transporters can significantly affect drug distribution, in particular for low permeable compounds. In this context transporter assays need to be prioritized for compounds with medium to low passive permeability. 

Factors analogous to those affecting gut absorption also can affect drug distribution and excretion. Any transporters or metabolizing enzymes can be taxed to capacity—which clearly would make the kinetic process nonlinear (see Linear versus Nonlinear Pharmacokinetics ). In order to have linear pharmacokinetics, all components (distribution, metabolism, filtration, active secretion, and active reabsorption) must be reasonably approximated by first-order kinetics for the valid design of controlled release delivery systems. 

Hwang CW, Wu D, Edelman ER, Physiological transport forces govern drug distribution for stent-based delivery. Circulation 2001 104(5) 600-605,... 

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