Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters
            <i>In Vitro</i>

Parvez, Masud; Kaisar, Nazia; Shin, Ho Jung; Lee, Yoon Jae; Shin, Jae‐Gook

doi:10.1128/aac.00512-18

Cited by 21 publications

(14 citation statements)

References 41 publications

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“…To this end, PK data obtained in critically ill children of different ages after the concomitant administration of clavulanic acid and amoxicillin was used. Each drug was assumed a probe for their specific elimination pathway, i.e., clavulanic acid for glomerular filtration (GF) and amoxicillin for a combination of GF and ATS through OAT1,3 ( 13 , 14 ). With this methodology the ontogeny function of OAT1,3 could be estimated.…”

Section: Introductionmentioning

confidence: 99%

Estimation of Ontogeny Functions for Renal Transporters Using a Combined Population Pharmacokinetic and Physiology-Based Pharmacokinetic Approach: Application to OAT1,3

Cristea

Krekels

Allegaert

et al. 2021

AAPS J

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To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CLR) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CLRpost-hoc values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CLR was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CLint,OAT1,3,invivo) and its ontogeny. CLint,OAT1,3,invivo ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CLR predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months–15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within ±50%). Using this novel approach, we estimated an in vivo functional ontogeny profile for CLint,OAT1,3,invivo that yields accurate CLR predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters.

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Section: Introductionmentioning

confidence: 99%

Estimation of Ontogeny Functions for Renal Transporters Using a Combined Population Pharmacokinetic and Physiology-Based Pharmacokinetic Approach: Application to OAT1,3

Cristea

Krekels

Allegaert

et al. 2021

AAPS J

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“…Moxifloxacin, which was characterized as a potent inhibitor of OCT1, could significantly inhibit the cellular transport of EMB ( Te Brake et al, 2016 ). Later, Parvez et al confirmed that EMB, amoxicillin, INH and prothionamide were novel substrates of OCT1 and as expected, the OCT1 inhibitor verapamil could strongly reduce their cellular uptake ( Parvez et al, 2018 ). In addition, they found that the DDI indices of OCT1-mediated uptake of EMB and prothionamide were similar to that of verapamil, suggesting a strong in vivo potential of DDIs for these drugs with others.…”

Section: Interaction Of Organic Cation Transporter 1 With Clinical mentioning

confidence: 76%

Drug-Drug Interactions at Organic Cation Transporter 1

2021

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The interaction between drugs and various transporters is one of the decisive factors that affect the pharmacokinetics and pharmacodynamics of drugs. The organic cation transporter 1 (OCT1) is a member of the Solute Carrier 22A (SLC22A) family that plays a vital role in the membrane transport of organic cations including endogenous substances and xenobiotics. This article mainly discusses the drug-drug interactions (DDIs) mediated by OCT1 and their clinical significance.

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“…Isoniazid has been reported to be a substrate of three solute carrier (SLC) transporters i.e. OCT2, OAT1, and OAT3 (35). These three SLC transporters are expressed in several tissues including brain and the blood-brain-barrier, and typically facilitate uptake of drug substrates (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…In our study, isoniazid showed a good distribution of drug over the blood-brain barrier, with median CSF-to-plasma ratios of 1.44 for fast acetylators and 1.48 for slow acetylators, resulting in a higher concentration in CSF than in plasma. Isoniazid has been reported to be a substrate of three solute carrier (SLC) transporters, i.e., OCT2, OAT1, and OAT3 ( 34 ). These three SLC transporters are expressed in several tissues, including brain tissue and the blood-brain barrier, and typically facilitate uptake of drug substrates (i.e., influx) into the central nervous system ( 35 , 36 ).…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

Panjasawatwong

Wattanakul

Hoglund

et al. 2020

Antimicrob Agents Chemother

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Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and are currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. One-hundred Vietnamese children with TBM were treated with an 8-month anti-tuberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs, and to simulate different dosing strategies. The pharmacokinetic properties of rifampicin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. CSF penetration of rifampicin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampicin, were sufficient to achieve target exposures. Ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampicin dosing at 50 mg/kg/day would be required to achieve the target exposure. Moreover, low rifampicin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampicin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.

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Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro

Cited by 21 publications

References 41 publications

Estimation of Ontogeny Functions for Renal Transporters Using a Combined Population Pharmacokinetic and Physiology-Based Pharmacokinetic Approach: Application to OAT1,3

Estimation of Ontogeny Functions for Renal Transporters Using a Combined Population Pharmacokinetic and Physiology-Based Pharmacokinetic Approach: Application to OAT1,3

Drug-Drug Interactions at Organic Cation Transporter 1

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

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