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What are drug transporters in pharmacokinetics?

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The interaction of drugs with various transporters in vivo is one of the determinants of the pharmacokinetic properties of drugs in vivo. The in vivo transport of drugs, including absorption, distribution, metabolism, and excretion processes, involves the permeability of drugs to biological membranes. The ability of drugs to permeate through biological membranes is mainly determined by their physicochemical properties, and lipophilicity is usually a key factor in determining the degree of drug absorption, hepatic transport, and brain permeation. However, sometimes increasing the lipophilicity of a drug does not necessarily increase the permeability of the biofilm to the drug. Further studies have shown that many tissues have a system of to-be-specialized transport proteins, called transporter, that mediate transmembrane transport.

Drug transporters play an important role in the absorption, distribution, metabolism, and excretion of drugs. Today, we will briefly understand the role of drug transporters in the process of drug transport in vivo. The purpose of pharmacokinetic studies in drug development is to reveal the absorption, distribution, and excretion of drugs and their metabolites in the body. The data can be used to explain and justify pharmacological and toxicological findings, and to design parameters for pharmacokinetic and toxicokinetic studies, such as AUC, half-life, clearance, etc.

Medicilon has extensive experience in pharmacokinetics. We offer a broad spectrum of high-quality services involving all micromolecule and macromolecule (protein and antibody), with service contents including in vitro ADME, in vivo pharmacokinetics, and bioanalysis. Results of in vivo pharmacokinetic studies in a wide range of laboratory animals including mice, rats, rabbits, pigs, dogs, and monkeys can help screen lead compounds.

Our Preclinical Pharmacokinetics Department has a number of professionals with rich theoretical knowledge and experimental experience for experiment design, experiment implementation, bioanalysis and data analysis. Our Pharmacokinetics Lab has passed the GLP certification by NMPA. Following the guiding principles of ICH, NMPA and FDA. The lab offers in vivo and in vitro pharmacokinetic tests according to the needs of our clients and provide them with complete sets of pharmacokinetic evaluation and optimization services. Our acclaimed quality data collection and efficient experiment can meet our clients’ needs from early drug discovery to new drug filing.

Medicilon's labs are certified by Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).webp

Role of drug transporters in drug absorption

Studies have shown that drug transporters are an important factor affecting the absorption of some drugs from the GI tract, and studying the role of transporters in absorption is important for improving the bioavailability of drugs and avoiding clinical drug interactions.

Some transporters can actively absorb amino acids, peptides, oligosaccharides, bile acids, and some water-soluble vitamins from the intestinal lumen into the blood vessels to increase the absorption of drugs. Other transporters actively drain drugs and exogenous substances from the intestinal epithelium into the intestinal lumen to reduce the intracellular drug concentration and restrict drug absorption, thus reducing drug efficacy. The main transporters in the intestinal epithelial cell membrane are P-GP, MRP, OATP, OCT, OAT, and other transporter families. Among them, P-GP is the most widely studied in active drug efflux from the gastrointestinal tract.

The role of drug transporters in drug distribution

The number and functional status of drug transporters have also been shown to significantly influence drug distribution. The distribution of transporters in some organs is closely related to the organ toxicity of drugs, and adequate studies on drug key transporters to analyze and assess the distribution characteristics of drug target tissues can help to determine more accurately the effects of drug exposure on drug efficacy and safety.

The role of drug transporters in hepatobiliary drug excretion

The liver plays a very important role in drug clearance and metabolism, and active uptake by the liver is an important process for hepatic drug clearance. Transporters in the hepatic sinusoidal tubule membrane and tubular membrane are involved in the transport of drugs and exogenous substances in the liver and bile. OATP is the main drug transporter for the hepatic uptake of organic anions and plays an important role in hepatobiliary excretion, especially in mediating hepatic absorption.

The role of drug transporters in drug excretion

Transporters are widely distributed in the excretory organs of the body and therefore play an important role in the excretion of drugs in vivo. Recent studies have shown that transporters are affected by various factors in mediating drug excretion, such as gene polymorphisms, drug interactions, disease, gender, species, etc. The effects are not only in the enhancement or inhibition of transporter function but also in the regulation of transporter expression.

The kidney plays a very important role in the elimination of many endogenous metabolites and drugs. Filtration of drugs by the glomerulus is a passive diffusion process, and tubular secretion and reabsorption, including both passive diffusion and active transport, with the active transport process mediated by many transporters. The active transport process is mediated by many transporters. Absorbent transporters, represented by OAT and OCT, absorb compounds in the interstitial tissues of the kidney and transport them to the tubular lumen; at the same time, efflux transporters, such as P-GP and MRP, are distributed in the renal tubules and prevent drug reabsorption.

A full range of services

Medicilon's experienced and comprehensive preclinical in vivo and ex vivo DMPK research team provides a wide range of services from early screening to IND filing studies for clients ranging from local start-ups to Top 10 global manufacturers, including metabolic stability, P450 enzyme inhibition, P450 enzyme induction, enzyme phenotyping, protein binding, erythrocyte/plasma partitioning ratio, Caco-2 permeability, transporter studies, metabolite identification, various genera and multiple routes of drug delivery PK, tissue distribution and blood-brain barrier permeability, excretion studies, in vivo drug interactions, multi-cycle cross BE/prescription screening, etc.

Medicilon's comprehensive training mechanism, comprehensive quality control (QC) system, and scientific and efficient project management system provide a strong guarantee for the efficient and high-quality completion of various DMPK projects.

In vitro ADME services

Plasma protein binding assay

Tissue protein binding assay

Whole blood/plasma ratio determination

Plasma Stability Test

Liver microsome stability tests

Hepatocyte metabolic stability tests

Metabolic phenotype research

CYP450 inhibition tests( TDI)

CYP450 induction tests

Caco-2 infiltration assay

Transporter (ABC and SLC) Assays

Drug-drug interaction

Metabolite identification, speculation

Estimation of a metabolic pathway

The in vivo process of a drug directly affects the concentration of the drug at its site of action and the time of maintaining the effective concentration, thus determining the onset, development, and disappearance of drug action. Therefore, the in vivo processes of drugs are the basis for the pharmacological effects and therapeutic effects of drugs and are the basis for the clinical formulation of drug regimens.

Medicilon’s in vivo PK services

Haemodynamics Research

Tissue distribution studies

Excretion Research

Material balance

Blood-brain barrier(BBB, Kp,uu)

Identification of metabolites in vivo

Isotope In Vitro Pharmacokinetic Assays

Isotope Tissue distribution studies

Isotope material balance studies

Peptide pharmacokinetic studies

PROTAC pharmacokinetic studies

ADC/PDC pharmacokinetic studies

Oligonucleotide pharmacokinetics

Pharmacokinetics of mRNA vaccines

Pharmacokinetics of cellular immunotherapy drugs

In vivo PK/TK assays

Pharmacokinetics is the study of absorption, distribution, metabolism, and excretion of drugs in the body and their time-dependent processes, while pharmacodynamics is the study of the kinetic process of drug effects over time and concentration. In vivo pharmacokinetics studies the absorption, distribution, metabolism, and excretion of drugs in living organisms, and the corresponding pharmacokinetic parameters are obtained through in vivo pharmacokinetic experiments in animals to reflect the process of drug changes occurring in vivo.

The traditional pharmacokinetics is to study the correspondence between concentration and effect in vitro, and the corresponding pharmacokinetic parameters, such as affinity and intrinsic activity, can be obtained according to the quantity-effect relationship of the drug. In vivo, due to the influence of drug absorption, distribution, and other pharmacokinetic factors, as well as physiological feedback regulation, the in vitro results, often do not reflect the in vivo results, and many phenomena cannot be explained by the traditional theory, such as the peak effect significantly lags behind the peak blood concentration, the duration of the drug effect is significantly longer than its retention time in the plasma, and the peak effect exceeds the blood concentration.

To address the above phenomena, a combined pharmacokinetic and pharmacodynamic model (PK-PD model) was developed, in which drug concentration and effect-time processes are measured simultaneously, and the corresponding pharmacokinetic parameters are analyzed through the organic combination of pharmacokinetic and pharmacodynamic models. These parameters can further reveal the regularity of the dynamic changes of drug effects in vivo and the mechanism of drug action, and reflect the comprehensive characteristics of pharmacokinetic and pharmacodynamic processes of drugs in vivo.

Medicilon offers in vivo PK/TK assay services

- Small molecule drugs and biologics

- PK experiments in rodents such as mice, rats, and golden rats; PK experiments in non-rodents such as beagle and non-human primates such as rhesus monkeys or crab-eating monkeys

- Different routes of administration: oral, gavage, intravenous, intraperitoneal, nasal spray, etc.

- Various intubation procedures

- Animal tissue distribution

- Identification of metabolites

- Pharmacokinetic experiments for early screening of new drugs

- Complete pharmacokinetic declaration tests

- Toxicokinetic studies according to GLP experimental requirements

Medicilon is one of the CRO to offer preclinical animal testing service for the global pharmaceutical companies in China.webp

Medicilon has about 30,000 square meters of animal housing, AAALAC certified to perform new biotech drug, macromolecule, and small molecule PK tests in mice, rats, rabbits, pigs, dogs, and monkeys, with sufficient animal supply to shorten the delivery time.

Medicilon has a high-standard animal house accredited by the International Association for Assessment and Accreditation of Laboratory Animal Management (AAALAC) and an animal use management system with IACUC regulation as the core. By implementing the 3R (Reduce, Replace, Optimize) principle through improved animal testing techniques and in vitro platforms, experimental quality and animal welfare are mutually reinforcing at Medicilon. For example, continuous micro blood collection from mice significantly reduces the number of animals used in PK experiments and the consumption of client supplies compared to traditional single-site or cross-collection methods and allows complete blood concentration profiles to be obtained from a single mouse, significantly reducing the errors introduced by individual differences compared to the traditional method of combining blood concentrations from up to 8 mice at different time points into a single curve.

Test cases

AnimalsDrug delivery regimenBlood collection points within 24 hoursNumber of animalsTest period
ICR miceSingle dose Intravenous/oral661-2 weeks
SD ratsSingle dose intravenous/oral6-1061-2 weeks
BeagleSingle dose intravenous/oral8-1061-2 weeks
Crab-eating monkeySingle dose intravenous/oral8-1061-2 weeks

Advanced bioanalytical platform

Medicilon is a new drug R&D CRO that introduced LC-MS/MS earlier in China, has continuously invested heavily in introducing high-end equipment in recent years, and has now built up:

The micromolecule analysis instrument platform represented by Sciex/Waters/Shimadzu ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and Thermo Q Exactive HF-X quadrupole/ultra-high-field Fourier transform ion trap high-resolution mass spectrometry;

The macromolecule analysis instrument platform represented by the MSD high-throughput multi-protein detector, Luminex liquid-phase chip protein analysis system, the Gyrolab nano-upgraded microfluidic immunoassay workstation, and the Applied Biosystems real-time fluorescent quantitative PCR system;

The sample pretreatment platform represented by the Covaris AFA adaptive focused acoustics high-performance sample processing system, the KingFisher Flex automatic magnetic bead extraction and purification system, the Lysera high-efficiency sample crusher, and the TurboVap high-speed sample concentrator;

The sample management platform is composed of Thermo/Panasonic ultra-low temperature refrigerators, the SensaTronics temperature monitoring system, and the Watson LIMS laboratory information management software.

Related Articles about "Pharmacokinetics Studies":

ADME Pharmacokinetics Studies

Pharmacokinetics and Pharmacodynamics (PK/PD) Studies

Drug Metabolism and Pharmacokinetics (DMPK) Studies

Pharmacokinetic Research Services

Factors Affecting Drug Metabolism

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