Shirley Tsunoda | University of California, San Diego (original) (raw)

Papers by Shirley Tsunoda

bioRxiv (Cold Spring Harbor Laboratory), Feb 2, 2024

PloS one, Mar 7, 2024

The Japanese national guidelines recommend significantly lower doses of carvedilol for heart fail... more The Japanese national guidelines recommend significantly lower doses of carvedilol for heart failure with reduced ejection fraction (HFrEF) management than the US guidelines. Using real-world data, we determined whether initial and target doses of carvedilol in Japanese patients (JPNs) differ from those in US patients (USPs), especially in Asian Americans (ASA) and Caucasians (CA), and investigated differences in outcomes. We collected data from the electronic medical records, including demographics, carvedilol dosing, tolerability, cardiac functional indicators like EF, cardiovascular events including all-cause deaths, and laboratory values from the

Circulation

Introduction: Carvedilol has improved cardiac mortality and morbidity for heart failure with redu... more Introduction: Carvedilol has improved cardiac mortality and morbidity for heart failure with reduced ejection fraction (HFrEF). The initial and target doses used in the Japanese randomized controlled trials (RCTs) were almost half of those in the USA leading to markedly lower recommended doses for HF management the in Japanese national guidelines compared to the USA. Hypothesis: Race may play a role in the optimal dose of carvedilol for HFrEF management. Methods: The international collaborative study was performed to compare the dose difference and the effect on heart functions, such as left ventricular EF (LVEF) and heart rate (HR), among Asian-Americans (AA), Caucasians (CA), and Japanese (JA) using real-world data. Each local ethics committee approved the study protocol at the University of California, San Diego (UCSD), the Osaka University Hospital (OUH), and the OU pharmaceutical sciences. The initial population at UCSD Health and OUH consisted of 1078 patients with HFrEF (≥ 20...

Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy

The Annals of pharmacotherapy, 1997

VOD is an important cause of morbidity and mortality in patients following allogeneic bone marrow... more VOD is an important cause of morbidity and mortality in patients following allogeneic bone marrow transplantation. Although VOD may improve in some patients, severe cases are often fatal. There is no established therapy to prevent progression to severe VOD; nor are there any conclusive or universally accepted methods for prevention of mortality associated with severe VOD. A treatment that could minimize hepatic damage and cause VOD to manifest as reversible liver damage rather than a progressive, fatal disease would indeed have a place in posttransplant therapy. Nontoxic ursodiol may play such a role by replacing hepatotoxic bile acids. Based on the limited available literature (2 studies), it is difficult to draw firm conclusions regarding the use of ursodiol to prevent VOD, although the preliminary results are promising. The studies, although small and not without weakness, suggested that ursodiol effectively reduces the incidence of VOD in allogeneic BMT patients. They do not, ho...

Clinical testing typically relies on invasive blood draws and biopsies. Alternative methods of sa... more Clinical testing typically relies on invasive blood draws and biopsies. Alternative methods of sample collection are continually being developed to improve patient experience; swabbing the skin is one of the least invasive sampling methods possible. To show that skin swabs in combination with untargeted mass spectrometry (metabolomics) can be used for non-invasive monitoring of an oral drug, we report the kinetics and metabolism of diphenhydramine in healthy volunteers (n=10) over the course of 24 hours in blood and three regions of the skin. Diphenhydramine and its metabolites were observed on the skin after peak plasma levels, varying by compound and skin location, and is an illustrative example of how systemically administered molecules can be detected on the skin surface. The observation of diphenhydramine directly from the skin supports the hypothesis that both parent drug and metabolites can be qualitatively measured from a simple non-invasive swab of the skin surface. The mec...

Clinical and Translational Science, 2021

Chemicals, including some systemically administered xenobiotics and their biotransformations, can... more Chemicals, including some systemically administered xenobiotics and their biotransformations, can be detected noninvasively using skin swabs and untargeted metabolomics analysis. We sought to understand the principal drivers that determine whether a drug taken orally or systemically is likely to be observed on the epidermis by using a random forest classifier to predict which drugs would be detected on the skin. A variety of molecular descriptors describing calculated properties of drugs, such as measures of volume, electronegativity, bond energy, and electrotopology, were used to train the classifier. The mean area under the receiver operating characteristic curve was 0.71 for predicting drug detection on the epidermis, and the SHapley Additive exPlanations (SHAP) model interpretation technique was used to determine the most relevant molecular descriptors. Based on the analysis of 2561 US Food and Drug Administration (FDA)‐approved drugs, we predict that therapeutic drug classes, such as nervous system drugs, are more likely to be detected on the skin. Detecting drugs and other chemicals noninvasively on the skin using untargeted metabolomics could be a useful clinical advancement in therapeutic drug monitoring, adherence, and health status.

Clinical Transplantation, 2020

Our objective was to evaluate physicians' perspectives on the clinical utility of pharmacogen... more Our objective was to evaluate physicians' perspectives on the clinical utility of pharmacogenetic (PGx) testing in kidney, liver, heart, and lung transplantation (KLHL‐Tx).

Annals of Pharmacotherapy, 1998

The theory that pruritus from cholestasis is due to increased opiate tone appears to have merit, ... more The theory that pruritus from cholestasis is due to increased opiate tone appears to have merit, based on the results of the clinical trials presented above. However, although opioid antagonists relieve itching to a large extent, the itching usually is not abolished completely. Several factors may explain this lack of complete relief. The doses used in the clinical trials may have been insufficient, or duration of therapy may have been short. It is also possible that nonopioid mechanisms contribute to pruritus from cholestasis. Although effective, naloxone therapy has several limitations for long-term use, including a short half-life and large first-pass metabolism, which necessitates parenteral administration. Intravenous administration is clearly not practical for a chronic disease. Nalmefene treatment has several advantages over naloxone, with both prolonged duration of action and increased potency at the opioid receptor level. However, nalmefene is available only as a parenteral product in the US. The nalmefene studies are limited by their small sample size and short follow-up periods. Additionally, two of the studies are available in abstract form only. Based on two clinical studies, naltrexone therapy appears promising. Gradual dose titration from 25 mg/d up to a maximum of 50 mg/d may minimize withdrawal reactions. Further long-term clinical trials using objective measures that compare opioid antagonists with other therapies are needed to clearly establish the role of these agents. Potential tachyphylaxis from long-term use of opioid antagonists requires further investigation. Combination therapy may also be required, since monotherapy with either opioid antagonists or other therapies have failed to completely relieve the pruritus caused by cholestasis. Given the potential for severe withdrawal reactions, opioid antagonists should be reserved for patients refractory to other treatments.

Human milk is the optimal infant nutrition. However, while human-derived metabolites such as lipi... more Human milk is the optimal infant nutrition. However, while human-derived metabolites such as lipids and oligosaccharides in human milk are regularly reported, the presence of exogenous chemicals (such as drugs, food, and synthetic compounds) are often not addressed. To understand the types of exogenous compounds that might be present, human milk (n=996) was analyzed by untargeted metabolomics. This analysis revealed that lifestyle molecules such as medications and their metabolites, food, industrial sources such as plasticizers, cosmetics, microbial molecules, and other personal care products are found in human milk. We provide further evidence that some of these lifestyle molecules are also detectable in the newborn's stool. Thus, this study gives important insight into the types of exposures infants receiving human milk might ingest due to the lifestyle choices, exposure, or medical status of the lactating parent.

Chemicals, including some systemically administered xenobiotics and their biotransformations, can... more Chemicals, including some systemically administered xenobiotics and their biotransformations, can be detected noninvasively using skin swabs and untargeted metabolomics analysis. We sought to understand the principal drivers that determine whether a drug taken orally or systemically is likely to be observed on the epidermis by using a random forest classifier to predict which drugs would be detected on the skin. A variety of molecular descriptors describing calculated properties of drugs, such as measures of volume, electronegativity, bond energy, and electrotopology, were used to train the classifier. The mean area under the ROC curve was 0.71 for predicting drug detection on the epidermis, and the SHapley Additive exPlanations model interpretation technique was used to determine the most relevant molecular descriptors. Based on the analysis of 2,561 FDA approved drugs, we predict that therapeutic drug classes such as nervous system drugs are more likely to be detected on the skin....

Clinical Pharmacology & Therapeutics (1999) 65, 172–172; doi:

Several new immunosuppressive agents have recently been approved for use in solid organ transplan... more Several new immunosuppressive agents have recently been approved for use in solid organ transplantation. Many of these agents have narrow therapeutic ranges, which necessitates drug concentration monitoring in order to optimise efficacy, minimise toxicity and individualise dosages. Some of the lessons learned with the clinical use of the revolutionary agent cyclosporin have been applied to the newer agents tacrolimus and sirolimus. The agent mycophenolate mofetil has been in clinical use without widespread drug concentration monitoring; however, recent data suggest that therapeutic monitoring may improve clinical outcomes, especially in certain high risk subsets of patients. This review focuses on the literature published to date on drug concentration monitoring of the newer immunosuppressive agents — tacrolimus, mycophenolate mofetil and sirolimus. In addition, pertinent aspects of the clinical pharmacokinetics and metabolism of each agent are reviewed.

Introduction: The scope of pharmacy practice has evolved over the last few decades to focus on th... more Introduction: The scope of pharmacy practice has evolved over the last few decades to focus on the optimization of medication therapy. Despite this positive impact, the lack of reimbursement remains a significant barrier to the implementation of innovative pharmacist practice models. Summary: We describe the successful development, implementation and outcomes of three types of pharmacist collaborative care models: (1) a pharmacist with physician oversight, (2) pharmacist–interprofessional teams and (3) physician–pharmacist teams. The outcome measurement of these pharmacist care models varied from the design phase to patient volume measurement and to comprehensive quality dashboards. All of these practice models have been successfully funded by affiliated health systems or grants. Conclusions: The expansion of pharmacist services delivered by clinical faculty has several benefits to affiliated health systems: (1) significant improvements in patient care quality, (2) access to experts...

Drug monitoring is crucial for providing accurate and effective care; however, current methods (e... more Drug monitoring is crucial for providing accurate and effective care; however, current methods (e.g., blood draws) are inconvenient and unpleasant. We aim to develop a non-invasive method for the detection and monitoring of drugs via human skin. The initial development toward this aim required information about which drugs, taken orally, can be detected via the skin. Untargeted liquid chromatography-mass spectrometry (LC-MS) was used as it was unclear if drugs, known drug metabolites, or other transformation products were detectable. In accomplishing our aim, we analyzed samples obtained by swabbing the skin of 15 kidney transplant recipients in five locations (forehead, nasolabial area, axillary, backhand, and palm), bilaterally, on two different clinical visits. Untargeted LC-MS data were processed using molecular networking via the Global Natural Products Social Molecular Networking platform. Herein, we report the qualitative detection and location of drugs and drug metabolites. ...

Clinical Pharmacokinetics

The trillions of microbes that make up the gut microbiome are an important contributor to health ... more The trillions of microbes that make up the gut microbiome are an important contributor to health and disease. With respect to xenobiotics, particularly orally administered compounds, the gut microbiome interacts directly with drugs to break them down into metabolic products. In addition, microbial products such as bile acids interact with nuclear receptors on host drug-metabolizing enzyme machinery, thus indirectly influencing drug disposition and pharmacokinetics. Gut microbes also influence drugs that undergo enterohepatic recycling by reversing host enzyme metabolic processes and increasing exposure to toxic metabolites as exemplified by the chemotherapy agent irinotecan and non-steroidal anti-inflammatory drugs. Recent data with immune checkpoint inhibitors demonstrate the impact of the gut microbiome on drug pharmacodynamics. We summarize the clinical importance of gut microbe interaction with digoxin, irinotecan, immune checkpoint inhibitors, levodopa, and non-steroidal anti-inflammatory drugs. Understanding the complex interactions of the gut microbiome with xenobiotics is challenging; and highly sensitive methods such as untargeted metabolomics with molecular networking along with other in silico methods and animal and human in vivo studies will uncover mechanisms and pathways. Incorporating the contribution of the gut microbiome to drug disposition, pharmacokinetics, and pharmacodynamics is vital in this era of precision medicine.

The effects of intramuscularly and orally administered medroxyprogesterone acetate on cytochrome ... more The effects of intramuscularly and orally administered medroxyprogesterone acetate on cytochrome P450 3A4 (CYP3A4) activity were investigated in twelve postmenopausal women in a randomized, crossover study. Unbound prednisolone clearance and the erythromycin breath test were used as markers of CYP3A4 activity. After 2 months of intramuscular progestin therapy, unbound prednisolone clearance increased by 25% in five of six subjects. Similarly, after intramuscular progestin therapy, results from the erythromycin breath test showed a 23% mean increase in CYP3A4 activity. In contrast, 2 months of oral progestin therapy had no effect on prednisolone pharmacokinetics or erythromycin metabolism. These results suggest that parenterally but not orally administered progestins may induce or activate the CYP3A4 enzyme system, leading to an increased metabolism of many CYP3A4 substrates.

bioRxiv (Cold Spring Harbor Laboratory), Feb 2, 2024

PloS one, Mar 7, 2024

The Japanese national guidelines recommend significantly lower doses of carvedilol for heart fail... more The Japanese national guidelines recommend significantly lower doses of carvedilol for heart failure with reduced ejection fraction (HFrEF) management than the US guidelines. Using real-world data, we determined whether initial and target doses of carvedilol in Japanese patients (JPNs) differ from those in US patients (USPs), especially in Asian Americans (ASA) and Caucasians (CA), and investigated differences in outcomes. We collected data from the electronic medical records, including demographics, carvedilol dosing, tolerability, cardiac functional indicators like EF, cardiovascular events including all-cause deaths, and laboratory values from the

Circulation

Introduction: Carvedilol has improved cardiac mortality and morbidity for heart failure with redu... more Introduction: Carvedilol has improved cardiac mortality and morbidity for heart failure with reduced ejection fraction (HFrEF). The initial and target doses used in the Japanese randomized controlled trials (RCTs) were almost half of those in the USA leading to markedly lower recommended doses for HF management the in Japanese national guidelines compared to the USA. Hypothesis: Race may play a role in the optimal dose of carvedilol for HFrEF management. Methods: The international collaborative study was performed to compare the dose difference and the effect on heart functions, such as left ventricular EF (LVEF) and heart rate (HR), among Asian-Americans (AA), Caucasians (CA), and Japanese (JA) using real-world data. Each local ethics committee approved the study protocol at the University of California, San Diego (UCSD), the Osaka University Hospital (OUH), and the OU pharmaceutical sciences. The initial population at UCSD Health and OUH consisted of 1078 patients with HFrEF (≥ 20...

Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy

The Annals of pharmacotherapy, 1997

VOD is an important cause of morbidity and mortality in patients following allogeneic bone marrow... more VOD is an important cause of morbidity and mortality in patients following allogeneic bone marrow transplantation. Although VOD may improve in some patients, severe cases are often fatal. There is no established therapy to prevent progression to severe VOD; nor are there any conclusive or universally accepted methods for prevention of mortality associated with severe VOD. A treatment that could minimize hepatic damage and cause VOD to manifest as reversible liver damage rather than a progressive, fatal disease would indeed have a place in posttransplant therapy. Nontoxic ursodiol may play such a role by replacing hepatotoxic bile acids. Based on the limited available literature (2 studies), it is difficult to draw firm conclusions regarding the use of ursodiol to prevent VOD, although the preliminary results are promising. The studies, although small and not without weakness, suggested that ursodiol effectively reduces the incidence of VOD in allogeneic BMT patients. They do not, ho...

Clinical testing typically relies on invasive blood draws and biopsies. Alternative methods of sa... more Clinical testing typically relies on invasive blood draws and biopsies. Alternative methods of sample collection are continually being developed to improve patient experience; swabbing the skin is one of the least invasive sampling methods possible. To show that skin swabs in combination with untargeted mass spectrometry (metabolomics) can be used for non-invasive monitoring of an oral drug, we report the kinetics and metabolism of diphenhydramine in healthy volunteers (n=10) over the course of 24 hours in blood and three regions of the skin. Diphenhydramine and its metabolites were observed on the skin after peak plasma levels, varying by compound and skin location, and is an illustrative example of how systemically administered molecules can be detected on the skin surface. The observation of diphenhydramine directly from the skin supports the hypothesis that both parent drug and metabolites can be qualitatively measured from a simple non-invasive swab of the skin surface. The mec...

Clinical and Translational Science, 2021

Chemicals, including some systemically administered xenobiotics and their biotransformations, can... more Chemicals, including some systemically administered xenobiotics and their biotransformations, can be detected noninvasively using skin swabs and untargeted metabolomics analysis. We sought to understand the principal drivers that determine whether a drug taken orally or systemically is likely to be observed on the epidermis by using a random forest classifier to predict which drugs would be detected on the skin. A variety of molecular descriptors describing calculated properties of drugs, such as measures of volume, electronegativity, bond energy, and electrotopology, were used to train the classifier. The mean area under the receiver operating characteristic curve was 0.71 for predicting drug detection on the epidermis, and the SHapley Additive exPlanations (SHAP) model interpretation technique was used to determine the most relevant molecular descriptors. Based on the analysis of 2561 US Food and Drug Administration (FDA)‐approved drugs, we predict that therapeutic drug classes, such as nervous system drugs, are more likely to be detected on the skin. Detecting drugs and other chemicals noninvasively on the skin using untargeted metabolomics could be a useful clinical advancement in therapeutic drug monitoring, adherence, and health status.

Clinical Transplantation, 2020

Our objective was to evaluate physicians' perspectives on the clinical utility of pharmacogen... more Our objective was to evaluate physicians' perspectives on the clinical utility of pharmacogenetic (PGx) testing in kidney, liver, heart, and lung transplantation (KLHL‐Tx).

Annals of Pharmacotherapy, 1998

The theory that pruritus from cholestasis is due to increased opiate tone appears to have merit, ... more The theory that pruritus from cholestasis is due to increased opiate tone appears to have merit, based on the results of the clinical trials presented above. However, although opioid antagonists relieve itching to a large extent, the itching usually is not abolished completely. Several factors may explain this lack of complete relief. The doses used in the clinical trials may have been insufficient, or duration of therapy may have been short. It is also possible that nonopioid mechanisms contribute to pruritus from cholestasis. Although effective, naloxone therapy has several limitations for long-term use, including a short half-life and large first-pass metabolism, which necessitates parenteral administration. Intravenous administration is clearly not practical for a chronic disease. Nalmefene treatment has several advantages over naloxone, with both prolonged duration of action and increased potency at the opioid receptor level. However, nalmefene is available only as a parenteral product in the US. The nalmefene studies are limited by their small sample size and short follow-up periods. Additionally, two of the studies are available in abstract form only. Based on two clinical studies, naltrexone therapy appears promising. Gradual dose titration from 25 mg/d up to a maximum of 50 mg/d may minimize withdrawal reactions. Further long-term clinical trials using objective measures that compare opioid antagonists with other therapies are needed to clearly establish the role of these agents. Potential tachyphylaxis from long-term use of opioid antagonists requires further investigation. Combination therapy may also be required, since monotherapy with either opioid antagonists or other therapies have failed to completely relieve the pruritus caused by cholestasis. Given the potential for severe withdrawal reactions, opioid antagonists should be reserved for patients refractory to other treatments.

Human milk is the optimal infant nutrition. However, while human-derived metabolites such as lipi... more Human milk is the optimal infant nutrition. However, while human-derived metabolites such as lipids and oligosaccharides in human milk are regularly reported, the presence of exogenous chemicals (such as drugs, food, and synthetic compounds) are often not addressed. To understand the types of exogenous compounds that might be present, human milk (n=996) was analyzed by untargeted metabolomics. This analysis revealed that lifestyle molecules such as medications and their metabolites, food, industrial sources such as plasticizers, cosmetics, microbial molecules, and other personal care products are found in human milk. We provide further evidence that some of these lifestyle molecules are also detectable in the newborn's stool. Thus, this study gives important insight into the types of exposures infants receiving human milk might ingest due to the lifestyle choices, exposure, or medical status of the lactating parent.

Chemicals, including some systemically administered xenobiotics and their biotransformations, can... more Chemicals, including some systemically administered xenobiotics and their biotransformations, can be detected noninvasively using skin swabs and untargeted metabolomics analysis. We sought to understand the principal drivers that determine whether a drug taken orally or systemically is likely to be observed on the epidermis by using a random forest classifier to predict which drugs would be detected on the skin. A variety of molecular descriptors describing calculated properties of drugs, such as measures of volume, electronegativity, bond energy, and electrotopology, were used to train the classifier. The mean area under the ROC curve was 0.71 for predicting drug detection on the epidermis, and the SHapley Additive exPlanations model interpretation technique was used to determine the most relevant molecular descriptors. Based on the analysis of 2,561 FDA approved drugs, we predict that therapeutic drug classes such as nervous system drugs are more likely to be detected on the skin....

Clinical Pharmacology & Therapeutics (1999) 65, 172–172; doi:

Several new immunosuppressive agents have recently been approved for use in solid organ transplan... more Several new immunosuppressive agents have recently been approved for use in solid organ transplantation. Many of these agents have narrow therapeutic ranges, which necessitates drug concentration monitoring in order to optimise efficacy, minimise toxicity and individualise dosages. Some of the lessons learned with the clinical use of the revolutionary agent cyclosporin have been applied to the newer agents tacrolimus and sirolimus. The agent mycophenolate mofetil has been in clinical use without widespread drug concentration monitoring; however, recent data suggest that therapeutic monitoring may improve clinical outcomes, especially in certain high risk subsets of patients. This review focuses on the literature published to date on drug concentration monitoring of the newer immunosuppressive agents — tacrolimus, mycophenolate mofetil and sirolimus. In addition, pertinent aspects of the clinical pharmacokinetics and metabolism of each agent are reviewed.

Introduction: The scope of pharmacy practice has evolved over the last few decades to focus on th... more Introduction: The scope of pharmacy practice has evolved over the last few decades to focus on the optimization of medication therapy. Despite this positive impact, the lack of reimbursement remains a significant barrier to the implementation of innovative pharmacist practice models. Summary: We describe the successful development, implementation and outcomes of three types of pharmacist collaborative care models: (1) a pharmacist with physician oversight, (2) pharmacist–interprofessional teams and (3) physician–pharmacist teams. The outcome measurement of these pharmacist care models varied from the design phase to patient volume measurement and to comprehensive quality dashboards. All of these practice models have been successfully funded by affiliated health systems or grants. Conclusions: The expansion of pharmacist services delivered by clinical faculty has several benefits to affiliated health systems: (1) significant improvements in patient care quality, (2) access to experts...

Drug monitoring is crucial for providing accurate and effective care; however, current methods (e... more Drug monitoring is crucial for providing accurate and effective care; however, current methods (e.g., blood draws) are inconvenient and unpleasant. We aim to develop a non-invasive method for the detection and monitoring of drugs via human skin. The initial development toward this aim required information about which drugs, taken orally, can be detected via the skin. Untargeted liquid chromatography-mass spectrometry (LC-MS) was used as it was unclear if drugs, known drug metabolites, or other transformation products were detectable. In accomplishing our aim, we analyzed samples obtained by swabbing the skin of 15 kidney transplant recipients in five locations (forehead, nasolabial area, axillary, backhand, and palm), bilaterally, on two different clinical visits. Untargeted LC-MS data were processed using molecular networking via the Global Natural Products Social Molecular Networking platform. Herein, we report the qualitative detection and location of drugs and drug metabolites. ...

Clinical Pharmacokinetics

The trillions of microbes that make up the gut microbiome are an important contributor to health ... more The trillions of microbes that make up the gut microbiome are an important contributor to health and disease. With respect to xenobiotics, particularly orally administered compounds, the gut microbiome interacts directly with drugs to break them down into metabolic products. In addition, microbial products such as bile acids interact with nuclear receptors on host drug-metabolizing enzyme machinery, thus indirectly influencing drug disposition and pharmacokinetics. Gut microbes also influence drugs that undergo enterohepatic recycling by reversing host enzyme metabolic processes and increasing exposure to toxic metabolites as exemplified by the chemotherapy agent irinotecan and non-steroidal anti-inflammatory drugs. Recent data with immune checkpoint inhibitors demonstrate the impact of the gut microbiome on drug pharmacodynamics. We summarize the clinical importance of gut microbe interaction with digoxin, irinotecan, immune checkpoint inhibitors, levodopa, and non-steroidal anti-inflammatory drugs. Understanding the complex interactions of the gut microbiome with xenobiotics is challenging; and highly sensitive methods such as untargeted metabolomics with molecular networking along with other in silico methods and animal and human in vivo studies will uncover mechanisms and pathways. Incorporating the contribution of the gut microbiome to drug disposition, pharmacokinetics, and pharmacodynamics is vital in this era of precision medicine.

The effects of intramuscularly and orally administered medroxyprogesterone acetate on cytochrome ... more The effects of intramuscularly and orally administered medroxyprogesterone acetate on cytochrome P450 3A4 (CYP3A4) activity were investigated in twelve postmenopausal women in a randomized, crossover study. Unbound prednisolone clearance and the erythromycin breath test were used as markers of CYP3A4 activity. After 2 months of intramuscular progestin therapy, unbound prednisolone clearance increased by 25% in five of six subjects. Similarly, after intramuscular progestin therapy, results from the erythromycin breath test showed a 23% mean increase in CYP3A4 activity. In contrast, 2 months of oral progestin therapy had no effect on prednisolone pharmacokinetics or erythromycin metabolism. These results suggest that parenterally but not orally administered progestins may induce or activate the CYP3A4 enzyme system, leading to an increased metabolism of many CYP3A4 substrates.