Table 6.

Drugs affecting mitochondrial carriers and mtDNA, their clinical manifestations, and relevant in vitro and in vivo studies.

Modules	Alterations	Pharmacology	Drugs	Clinical Manifestations	Cmax	Models	Dose	Time	References
Carrier	Downregulation of CPT I expression	Alkylating agent	Cyclophosphamide	HMC, CMP	143 μM	Male Wistar rats (IP)	200 mg/kg	10 d	[189]
Carrier	Downregulation of CPT I expression	Anesthesia	Propofol	HF, arrhythmia	30.13 μM	HiPSC-CMs	10 µg/mL	48 h	[163]
Carrier	Downregulation of CPT I expression	TKIs	Sunitinib	Decreased LVEF, QT prolongation, TdP, hypertension, HF, CMP	0.25 μM	Rats (oral)	25 mg/kg/d	28 d	[173]
Carrier	Inhibition of CPT1 activity	Anti-arrhythmic drug	Dronedarone	AF, HF	0.15–0.26 μM	Isolated rat heart mitochondria	IC50 = 40 µM	20 min	[139]
Carrier	loss of carnitine	Co-catalyst	Pivalic acid	CMP					[232]
Carrier	Inhibition of ANT	NSAIDs	Diclofenac	Hypertension, arrhythmias	7.9 µM	Submitochondrial particles	314 nM/mg protein diminished 76%		[142]
			Nimesulide			Submitochondrial particles	259 nM/mg protein diminished 60%		[142]
Carrier	Inhibition of ANT	NRTIs	Zidovudine	CMP	4 μM				[233]
mtDNA	Inhibition of mitochondrial DNA polymerase	NRTIs	Zidovudine	CMP	4 μM	Cardiac DNA pol-γ	1 µM		[234]
mtDNA	Inhibition of topoisomerase II	Anthracyclines	DOX	CHF, decreased LVEF, ST, myocarditis, CMP	15.3 μM	-	-	-	[235]
			Daunorubicin	CMP, MI, CHF, VA, pericarditis, myocarditis	89 μM	-	-	-	[207]
			Idarubicin	CMP, MI, CHF, VA, decreased LVEF	23.22 μM	-	-	-	[207]
mtDNA	Inhibition of topoisomerase II	Chemotherapeutic agents	Mitoxantrone	CHF, CMP, decreased LVEF, arrhythmia	3.3 μM	-	-	-	[215]
mtDNA	mtDNA content decreasing	Anthracyclines	DOX	CHF, decreased LVEF, ST, myocarditis, CMP	15.3 μM	Male Wistar rats (IV)	1 mg/kg/w	7 w (started at 11 w, observed at 48 w)	[96]
mtDNA	mtDNA content decreasing	TKIs	Regorafenib	MI; hypertension	8.08 μM	H9c2	5 μM	72 h	[90]

Abbreviations: NRTIs: nucleoside reverse transcriptase inhibitors; NSAIDs: nonsteroidal anti-inflammatory drugs; TKIs: tyrosine kinase inhibitors; ANT: mitochondrial ADP/ATP transport; TCA: tricarboxylic acid; DOX: doxorubicin; CHF: congestive heart failure; LVEF: left ventricular ejection fraction; HF: heart failure; TdP: torsades de pointes; MI: myocardial infarction; AF: atrial fibrillation; CMP: cardiomyopathy; ST: sinus tachycardia; HMC: hemorrhagic myocarditis; VA: ventricular arrhythmia; HA: heart attack; IP: intraperitoneal; IV: intravenously; BID: twice daily; w: week; d: day; h: hours.