Interplay of gender, age and drug properties on reporting frequency of drug-induced liver injury

George, Nayana; Chen, Minjun; Yuen, Nancy A.; Hunt, Christine M.; Suzuki, Ayako

doi:10.1016/j.yrtph.2018.01.018

Cited by 37 publications

(36 citation statements)

References 39 publications

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“…In these large studies, women displayed higher toxicity rates by up to 15% as compared to men 9,52–54 . Consistently with these findings, a data mining analysis of global liver safety reports was conducted for 375 drugs associated with hepatotoxicity, from WHO VigiBaseTM 55 . A higher overall liver event reporting for women and a higher reporting of acute liver failure for younger women were identified 56 .…”

Section: Discussionmentioning

confidence: 89%

Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity - implications for mechanistic pharmacokinetics modeling

Okyar

Kumar

Filipski

et al. 2019

Sci Rep

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P-glycoprotein ( P-gp ) largely influences the pharmacokinetics (PK) and toxicities of xenobiotics in a patient-specific manner so that personalized drug scheduling may lead to significant patient’s benefit. This systems pharmacology study investigated P-gp activity in mice according to organ, sex, feeding status, and circadian time. Sex-specific circadian changes were found in P-gp ileum mRNA and protein levels, circadian amplitudes being larger in females as compared to males. Plasma, ileum and liver concentrations of talinolol, a pure P-gp substrate, significantly differed according to sex, feeding and circadian timing. A physiologically-based PK model was designed to recapitulate these datasets. Estimated mesors (rhythm-adjusted mean) of ileum and hepatic P-gp activity were higher in males as compared to females. Circadian amplitudes were consistently higher in females and circadian maxima varied by up to 10 h with respect to sex. Fasting increased P-gp activity mesor and dampened its rhythm. Ex-vivo bioluminescence recordings of ileum mucosae from transgenic mice revealed endogenous circadian rhythms of P-gp protein expression with a shorter period, larger amplitude, and phase delay in females as compared to males. Importantly, this study provided model structure and parameter estimates to refine PK models of any P-gp substrate to account for sex, feeding and circadian rhythms.

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Section: Discussionmentioning

confidence: 89%

Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity - implications for mechanistic pharmacokinetics modeling

Okyar

Kumar

Filipski

et al. 2019

Sci Rep

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“…In vivo animal studies, sex differences in susceptibility to DILI 399 depends on models: male dominance in liver injury induced by acetaminophen [80][81][82] and cocaine 400 (only after the onset of puberty) 83,84 and female dominance in halothane [85][86][87][88] and in another 401 immune-mediated DILI model 89 . In humans, age, sex, and a proxy of women's menopausal status 402 (i.e., 50 years) significantly influence drug-specific reporting frequencies of liver events in the 403 World Health Organization VigiBase™ 90,91 , and influence clinical and histologic phenotypes of 404 DILI 92,93 . Drugs associated with sex-/age-biased reporting frequencies of liver events showed 405 distinct properties 90 .…”

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confidence: 99%

“…In humans, age, sex, and a proxy of women's menopausal status 402 (i.e., 50 years) significantly influence drug-specific reporting frequencies of liver events in the 403 World Health Organization VigiBase™ 90,91 , and influence clinical and histologic phenotypes of 404 DILI 92,93 . Drugs associated with sex-/age-biased reporting frequencies of liver events showed 405 distinct properties 90 . For example, drug properties such as mitochondrial toxicity, reactive 406 metabolite formation, and BSEP inhibition are more prevalent among drugs with women-biased 407 reporting frequencies 90 .…”

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confidence: 99%

“…Drugs associated with sex-/age-biased reporting frequencies of liver events showed 405 distinct properties 90 . For example, drug properties such as mitochondrial toxicity, reactive 406 metabolite formation, and BSEP inhibition are more prevalent among drugs with women-biased 407 reporting frequencies 90 . Drug properties of high lipophilicity, biliary excretion, higher 408 transporter inhibitions, Cmax (the maximum serum concentration that a drug achieves ) and 409 plasma protein binding, yet shorter plasma elimination are more prevalent among drugs with 410 old age-biased reporting frequencies 90,91 .…”

mentioning

confidence: 99%

“…For example, drug properties such as mitochondrial toxicity, reactive 406 metabolite formation, and BSEP inhibition are more prevalent among drugs with women-biased 407 reporting frequencies 90 . Drug properties of high lipophilicity, biliary excretion, higher 408 transporter inhibitions, Cmax (the maximum serum concentration that a drug achieves ) and 409 plasma protein binding, yet shorter plasma elimination are more prevalent among drugs with 410 old age-biased reporting frequencies 90,91 . In addition, drug properties, host factors, and their 411 specific interactions can influence a likelihood of delayed onset of DILI 94 102 .…”

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confidence: 99%

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Drug-induced liver injury

Aithal

2019

Medicine

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Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when the subject is exposed to toxic doses of some compounds (acetaminophen overdose) or in an unpredictable way with many drugs in common use. Drugs can be harmful to the liver in a susceptible subject on the background of genetic and environmental factors. This accounts for modifications in the hepatic metabolism and excretion of the agent leading to cellular stress, direct cell death, activation of an adaptive immune response and a failure to adapt with progression to overt liver injury. Idiosyncratic DILI is a relative rare liver disorder but can be severe and even fatal, presenting with a variety of phenotypes, which mimic almost every other liver disease. Diagnosis of DILI relies on the exclusion of other etiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need a refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has yet been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune checkpoint inhibitors.

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Clinical Characteristics and Outcome of Drug‐Induced Liver Injury in the Older Patients: From the Young‐Old to the Oldest‐Old

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Robles‐Díaz

Ortega‐Alonso

et al. 2020

Clin Pharma and Therapeutics

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Older patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥ 65 years) were categorized according to age: "young" (< 65 years); "young-old" (65-74 years); "middle-old" (75-84 years); and "oldest-old" (≥ 85 years). All elderly groups had an increasingly higher comorbidity burden (P < 0.001) and polypharmacy (P < 0.001). There was a relationship between jaundice and hospitalization (P < 0.001), and both were more prevalent in the older age groups, especially in the oldest-old (88% and 69%, respectively), and the DILI episode was more severe (P = 0.029). The proportion of females decreased across age groups from the young to the middle-old, yet in the oldest-old there was a distinct female predominance. Pattern of liver injury shifted towards cholestatic with increasing age among top culprit drugs amoxicillin-clavulanate, atorvastatin, levofloxacin, ibuprofen, and ticlopidine. The best cutoff point for increased odds of cholestatic DILI was 65 years. Older patients had increased non-liver-related mortality (P = 0.030) as shown by the predictive capacity of the Model for End-Stage Liver Disease score (odds ratio (OR) = 1.116; P < 0.001), and comorbidity burden (OR = 4.188; P = 0.001) in the 6-month mortality. Older patients with DILI exhibited an increasingly predominant cholestatic phenotype across a range of culprit drugs, other than amoxicillin-clavulanate, with increased non-liver-related mortality and require a different approach to predict outcome. The oldest DILI patients exhibited a particular phenotype with more severe DILI episodes and need to be considered when stratifying older DILI populations.

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Interplay of gender, age and drug properties on reporting frequency of drug-induced liver injury

Cited by 37 publications

References 39 publications

Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity - implications for mechanistic pharmacokinetics modeling

Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity - implications for mechanistic pharmacokinetics modeling

Drug-induced liver injury

Clinical Characteristics and Outcome of Drug‐Induced Liver Injury in the Older Patients: From the Young‐Old to the Oldest‐Old

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